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Song R, Yin S, Wu J, Yan J. Neuronal regulated cell death in aging-related neurodegenerative diseases: key pathways and therapeutic potentials. Neural Regen Res 2025; 20:2245-2263. [PMID: 39104166 PMCID: PMC11759035 DOI: 10.4103/nrr.nrr-d-24-00025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/13/2024] [Accepted: 06/18/2024] [Indexed: 08/07/2024] Open
Abstract
Regulated cell death (such as apoptosis, necroptosis, pyroptosis, autophagy, cuproptosis, ferroptosis, disulfidptosis) involves complex signaling pathways and molecular effectors, and has been proven to be an important regulatory mechanism for regulating neuronal aging and death. However, excessive activation of regulated cell death may lead to the progression of aging-related diseases. This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases. Notably, the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases. These forms of cell death exacerbate disease progression by promoting inflammation, oxidative stress, and pathological protein aggregation. The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms, with a focus on ferroptosis, cuproptosis, and disulfidptosis. For instance, FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation, while copper mediates glutathione peroxidase 4 degradation, enhancing ferroptosis sensitivity. Additionally, inhibiting the Xc- transport system to prevent ferroptosis can increase disulfide formation and shift the NADP + /NADPH ratio, transitioning ferroptosis to disulfidptosis. These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms. In conclusion, identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.
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Affiliation(s)
- Run Song
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
| | - Shiyi Yin
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
| | - Jiannan Wu
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
| | - Junqiang Yan
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
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Ling Z, Kong Q, He Z, Hao X, Liu R, Liu J, Wang Y, Liu J, Du W, Liu Y. Hydrogen sulfide improves depression-like behaviors in CUMS-induced mice by regulating autophagy. Psychoneuroendocrinology 2025; 175:107418. [PMID: 40023886 DOI: 10.1016/j.psyneuen.2025.107418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 02/18/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
The pathogenesis of depression is associated with synaptic impairment and dysfunction in autophagy processes. Mendelian randomization (MR) analysis revealed that six GWAS IDs revealed a significant association between Beclin-1 levels and depression risk. Besides, all SNPs had a positive effect on depression risk. Analyzing neurons from depressed individuals using single-cell RNA sequencing (scRNA-seq) uncovered decreased expression of AKT, mTOR, and genes linked to synaptic plasticity. The activation of the PI3K/AKT/mTOR signaling has been demonstrated to control autophagy and have a protective effect on the nervous system. Hydrogen sulfide (H2S) is an endogenous gasotransmitter that can potentially treat various neurological disorders by improving neuronal synaptic plasticity. However, whether H2S regulates autophagy through PI3K/AKT/mTOR signaling, improves neuronal synaptic plasticity damage, and plays an antidepressant role is unclear. Our current research revealed that the reduction in the expression of p-PI3K, p-AKT, and p-mTOR proteins increase in neuronal autophagy activity and decline synaptic plasticity in mice with depression induced by chronic unpredictable mild stress (CUMS). Treatment with the exogenous hydrogen sulfide donor NaHS for one day and continuous treatment for one week improved the depression-like behaviors in the mice. Compared with those after one day of NaHS treatment, the above protein expression levels were restored and maintained, and the antidepressant effect was more significant after one week of continuous treatment with NaHS. Moreover, the PI3K inhibitor LY294002 was used to demonstrate that NaHS suppresses autophagy through activating the PI3K/AKT/mTOR signaling and ameliorates synaptic plasticity impairments. This study provides novel insights into the antidepressant mechanisms of H2S, highlighting its antidepressant therapeutic potential.
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Affiliation(s)
- Zhaoke Ling
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Qingqing Kong
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Zhiqiang He
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xin Hao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Ruiyao Liu
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Jie Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Yushi Wang
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jiao Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Wenlong Du
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
| | - Yi Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
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Li L, Gu L, Hua Y, Xu H, Ling Y, Tong L, Chen M, Ma R. Kumatakenin alleviates depressive-like behaviors by suppressing excessive autophagy in hippocampus via ATG5. Eur J Pharmacol 2025; 999:177688. [PMID: 40294778 DOI: 10.1016/j.ejphar.2025.177688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/25/2025] [Accepted: 04/25/2025] [Indexed: 04/30/2025]
Abstract
The prevalence of depression has been escalating annually, imposing a substantial burden on both individuals and society. Radix Astragali, a multifaceted herb utilized in traditional Chinese medicine, has been employed in clinical settings for the treatment of depression. Kumatakenin, a principal active constituent of Radix Astragali, has yet to be thoroughly investigated for its potential antidepressant effects. In this study, we elucidated a novel effect of Kumatakenin, which ameliorated depression-like behaviors by modulating excessive autophagy in the hippocampus of mice exhibiting depressive symptoms. Utilizing transmission electron microscopy, we identified a significant increase in autophagosomes within the hippocampal region of depressed mice, which was notably reduced following Kumatakenin administration. Further, molecular docking analyses revealed an interaction between Kumatakenin and autophagy-related gene 5 (ATG5). At the protein level, Kumatakenin administration resulted in a marked decrease in microtubule-associated protein 1 light chain 3 (LC3) and ATG5 levels within hippocampal tissues. At the cellular level, in a corticosterone (CORT)-induced cell model, Kumatakenin significantly diminished the levels of LC3 and ATG5. Upon overexpression of ATG5 through lentiviral transfection, the ability of Kumatakenin to reduce LC3 and ATG5 levels was nullified. These observations suggested that Kumatakenin exerted its antidepressant effects by decreasing LC3 and ATG5 concentrations in hippocampal tissues.
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Affiliation(s)
- Lei Li
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
| | - Ling Gu
- School of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
| | - Yang Hua
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
| | - Huiying Xu
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
| | - Yuyan Ling
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
| | - Lijun Tong
- Medical Laboratory Department, Inner Mongolia Autonomous Region Mental Health Center, Hohhot, 010010, PR China.
| | - Meijuan Chen
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
| | - Ruiting Ma
- Medical Laboratory Department, Inner Mongolia Autonomous Region Mental Health Center, Hohhot, 010010, PR China.
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Grahl MVC, Hohl KS, Smaniotto T, Carlini CR. Microbial Trojan Horses: Virulence Factors as Key Players in Neurodegenerative Diseases. Molecules 2025; 30:687. [PMID: 39942791 PMCID: PMC11820544 DOI: 10.3390/molecules30030687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/01/2025] [Accepted: 02/01/2025] [Indexed: 02/16/2025] Open
Abstract
Changes in population demographics indicate that the elderly population will reach 2.1 billion worldwide by 2050. In parallel, there will be an increase in neurodegenerative diseases such as Alzheimer's and Parkinson's. This review explores dysbiosis occurring in these pathologies and how virulence factors contribute to the worsening or development of clinical conditions, and it summarizes existing and potential ways to combat microorganisms related to these diseases. Microbiota imbalances can contribute to the progression of neurodegenerative diseases by increasing intestinal permeability, exchanging information through innervation, and even acting as a Trojan horse affecting immune cells. The microorganisms of the microbiota produce virulence factors to protect themselves from host defenses, many of which contribute to neurodegenerative diseases. These virulence factors are expressed according to the genetic composition of each microorganism, leading to a wide range of factors to be considered. Among the main virulence factors are LPS, urease, curli proteins, amyloidogenic proteins, VacA, and CagA. These factors can also be packed into bacterial outer membrane vesicles, which transport proteins, RNA, and DNA, enabling distal communication that impacts various diseases, including Alzheimer's and Parkinson's.
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Affiliation(s)
- Matheus V. C. Grahl
- Graduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90619-900, RS, Brazil
| | - Kelvin Siqueira Hohl
- Graduate Program in Biochemistry, Institute of Health Basic Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (K.S.H.); (T.S.)
| | - Thiago Smaniotto
- Graduate Program in Biochemistry, Institute of Health Basic Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (K.S.H.); (T.S.)
| | - Célia R. Carlini
- Center of Biotechnology, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre 91501-970, RS, Brazil
- Graduate Program of Biosciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
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Wright EB, Larsen EG, Padilla-Rodriguez M, Langlais PR, Bhattacharya MRC. Neuronal endolysosomal acidification relies on interactions between transmembrane protein 184B (TMEM184B) and the vesicular proton pump. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.01.635992. [PMID: 39975166 PMCID: PMC11838497 DOI: 10.1101/2025.02.01.635992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Disruption of endolysosomal acidification is a hallmark of several neurodevelopmental and neurodegenerative disorders. Impaired acidification causes accumulation of toxic protein aggregates and disrupts neuronal homeostasis, yet the molecular mechanisms regulating endolysosomal pH in neurons remain poorly understood. A critical regulator of lumenal acidification is the vacuolar ATPase (V-ATPase), a proton pump whose activity depends on dynamic assembly of its V0 and V1 subdomains. In this study, we identify transmembrane protein 184B (TMEM184B) as a novel regulator of endolysosomal acidification in neurons. TMEM184B is an evolutionarily conserved 7-pass transmembrane protein required for synaptic structure and function, and sequence variation in TMEM184B causes neurodevelopmental disorders, but the mechanism for this effect is unknown. We performed proteomic analysis of TMEM184B-interacting proteins and identified enrichment of components involved in endosomal trafficking and function, including the V-ATPase. TMEM184B localizes to early and late endosomes, further supporting a role in the endosomal system. Loss of TMEM184B results in significant reductions in endolysosomal acidification within cultured mouse cortical neurons. This alteration in pH is associated with impaired assembly of the V-ATPase V0 and V1 subcomplexes in the TMEM184B mutant mouse brain, suggesting a mechanism by which TMEM184B promotes flux through the endosomal pathway. Overall, these findings identify a new contributor in maintaining endosomal function and provide a mechanistic basis for disrupted neuronal function in human TMEM184B-associated nervous system disorders. Significance Statement Endolysosomal acidification is essential for neuronal protein homeostasis, yet its regulation in neurons remains poorly understood. Here, we identify TMEM184B as a key regulator of this process, establishing its first known cellular role. We show that TMEM184B interacts with vacuolar ATPase (V-ATPase) components and promotes the assembly of its V0 and V1 subdomains, facilitating lumenal acidification. Loss of TMEM184B disrupts endolysosomal pH in neurons, potentially impairing proteostasis. These findings reveal a critical function for TMEM184B in neuronal maintenance and provide mechanistic insight into its link to neurological disorders. This work advances our understanding of endolysosomal regulation and suggests TMEM184B regulation could improve outcomes in diseases involving lysosomal dysfunction.
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Riordan R, Saxton A, Han M, McMillan PJ, Kow RL, Liachko NF, Kraemer BC. TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy in transgenic Caenorhabditis elegans. Alzheimers Dement 2025; 21:e14468. [PMID: 39711302 PMCID: PMC11848199 DOI: 10.1002/alz.14468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 10/28/2024] [Accepted: 11/17/2024] [Indexed: 12/24/2024]
Abstract
INTRODUCTION Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for several neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD). The C-terminal (CT) domain of TMEM106B occurs as fibrillar protein deposits in the brains of dementia patients. METHODS To determine the TMEM CT aggregation propensity and neurodegenerative potential, we generated transgenic Caenorhabditis elegans expressing the human TMEM CT fragment aggregating in FTLD cases. RESULTS Pan-neuronal expression of human TMEM CT in C. elegans causes severe neuronal dysfunction driving neurodegeneration. Cytosolic aggregation of TMEM CT proteins accompanied by behavioral dysfunction and neurodegeneration. Loss of pgrn-1 did not modify TMEM CT phenotypes suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. The mechanistic drivers of TMEM106B proteinopathy appear distinct from known modifiers of tauopathy. DISCUSSION Our data demonstrate that TMEM CT aggregation can kill neurons. TMEM106B transgenic C.elegans provide a useful model for characterizing TMEM106B proteinopathy-mediated neurodegeneration in FTLD. HIGHLIGHTS Pan-neuronal expression of human TMEM106B C-terminal fragments (TMEM CT) in C. elegans neurons drives a suite of disease-related phenotypes useful for modeling the molecular and cellular features of TMEM106B neuropathology. TMEM CT expression results in extensive TMEM aggregation and accumulation of highly detergent insoluble protein species. TMEM CT expression causes moderate to severe neuronal dysfunction dependent on TMEM CT abundance as measured by stereotypical behavioral readouts. TMEM CT expression drives significant neurodegenerative changes. Dendra2 tagged TMEM exhibits similar properties to untagged TMEM allowing ready visualization of the protein. TMEM CT aggregates accumulate adjacent to but not within lysosomes. PGRN loss of function does not impact TMEM CT toxicity. Modifiers of tau and TDP-43 proteinopathies have little impact on TMEM CT-related neurodegenerative phenotypes.
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Affiliation(s)
- Ruben Riordan
- Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care SystemSeattleWashingtonUSA
- Division of Gerontology and Geriatric MedicineDepartment of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Aleen Saxton
- Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care SystemSeattleWashingtonUSA
| | - Marina Han
- Division of Gerontology and Geriatric MedicineDepartment of MedicineUniversity of WashingtonSeattleWashingtonUSA
- Graduate Program in NeuroscienceUniversity of WashingtonSeattleWashingtonUSA
| | - Pamela J. McMillan
- Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care SystemSeattleWashingtonUSA
- Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleWashingtonUSA
| | - Rebecca L. Kow
- Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care SystemSeattleWashingtonUSA
- Division of Gerontology and Geriatric MedicineDepartment of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Nicole F. Liachko
- Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care SystemSeattleWashingtonUSA
- Division of Gerontology and Geriatric MedicineDepartment of MedicineUniversity of WashingtonSeattleWashingtonUSA
- Graduate Program in NeuroscienceUniversity of WashingtonSeattleWashingtonUSA
| | - Brian C. Kraemer
- Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care SystemSeattleWashingtonUSA
- Division of Gerontology and Geriatric MedicineDepartment of MedicineUniversity of WashingtonSeattleWashingtonUSA
- Graduate Program in NeuroscienceUniversity of WashingtonSeattleWashingtonUSA
- Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleWashingtonUSA
- Department of Laboratory Medicine and PathologyUniversity of WashingtonSeattleWashingtonUSA
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Sui H, Sun Z, Liu C, Xi H. Ferritinophagy promotes microglia ferroptosis to aggravate neuroinflammation induced by cerebral ischemia-reperfusion injury via activation of the cGAS-STING signaling pathway. Neurochem Int 2025; 183:105920. [PMID: 39732341 DOI: 10.1016/j.neuint.2024.105920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/12/2024] [Accepted: 12/17/2024] [Indexed: 12/30/2024]
Abstract
Cerebral ischemia-reperfusion injury (CIRI) is a common and serious complication of reperfusion therapy in patients with ischemic stroke (IS). The regulation of microglia-mediated neuroinflammation to control CIRI has garnered considerable attention. The balance of iron metabolism is key to maintaining the physiological functions of microglia. Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy, an important pathway in regulating iron metabolism, is a promising intervention target. However, studies on the impacts of ferritinophagy on microglia-mediated neuroinflammation are lacking. This study aimed to identify potential treatments for CIRI-induced neuroinflammation by focusing on ferritinophagy and the specific mechanisms whereby iron metabolism regulates microglia-mediated neuroinflammation. CIRI induced the activation of ferritinophagy in microglia, characterized by the upregulation of NCOA4, downregulation of Ferritin Heavy Chain 1 (FTH1), and increased intracellular iron levels. This activation contributes to increased ferroptosis, oxidative stress, and the release of inflammatory factors. Silencing NCOA4 or application of the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively suppressed the CIRI-induced damage in vivo and in vitro. While Fer-1 addition did not inhibit the CIRI-activated ferritinophagy, it did partially reverse the alleviation of NCOA4 depletion-induced neuroinflammation, suggesting that ferroptosis is an essential intermediate step in ferritinophagy-induced neuroinflammatory damage. Furthermore, using IS-related transcriptomic data, the cGAS-STING pathway was identified as a crucial mechanism connecting ferritinophagy and ferroptosis. Specific inhibition of the cGAS-STING pathway reduced ferritinophagy-induced ferroptosis and neuroinflammation. In summary, our results indicated that ferritinophagy activates the cGAS-STING signaling pathway, which promotes the inflammatory response and oxidative stress in microglia in a ferroptosis-dependent manner, thereby exacerbating CIRI-induced neuroinflammation. These findings provide theoretical support for the clinical treatment of CIRI.
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Affiliation(s)
- Haijing Sui
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, Harbin, 150001, China
| | - Zhenyu Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, Harbin, 150001, China
| | - Chang Liu
- Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, 150001, China
| | - Hongjie Xi
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, Harbin, 150001, China.
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Hao M, Chu J, Zhang T, Yin T, Gu Y, Liang W, Ji W, Zhuang J, Liu Y, Gao J, Yin Y. Nanomaterials-mediated lysosomal regulation: a robust protein-clearance approach for the treatment of Alzheimer's disease. Neural Regen Res 2025; 20:424-439. [PMID: 38819046 PMCID: PMC11317947 DOI: 10.4103/nrr.nrr-d-23-01736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 01/04/2024] [Accepted: 02/20/2024] [Indexed: 06/01/2024] Open
Abstract
Alzheimer's disease is a debilitating, progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins, including amyloid plaques and intracellular tau tangles, primarily within the brain. Lysosomes, crucial intracellular organelles responsible for protein degradation, play a key role in maintaining cellular homeostasis. Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases, including Alzheimer's disease. Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer's disease. Currently, the efficacy of drugs in treating Alzheimer's disease is limited, with major challenges in drug delivery efficiency and targeting. Recently, nanomaterials have gained widespread use in Alzheimer's disease drug research owing to their favorable physical and chemical properties. This review aims to provide a comprehensive overview of recent advances in using nanomaterials (polymeric nanomaterials, nanoemulsions, and carbon-based nanomaterials) to enhance lysosomal function in treating Alzheimer's disease. This review also explores new concepts and potential therapeutic strategies for Alzheimer's disease through the integration of nanomaterials and modulation of lysosomal function. In conclusion, this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer's disease. The application of nanotechnology to the development of Alzheimer's disease drugs brings new ideas and approaches for future treatment of this disease.
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Affiliation(s)
- Mengqi Hao
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Jianjian Chu
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
| | - Tinglin Zhang
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Tong Yin
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
| | - Yuankai Gu
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
| | - Wendanqi Liang
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Wenbo Ji
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
| | - Jianhua Zhuang
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
| | - Yan Liu
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Gao
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - You Yin
- Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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Yang D, Sun R, Sun H, Li Q, Zhang H, Zhang X, Shi L, Yao L, Tang Y. A FRET biosensor constructed using pH sensitive G-quadruplex DNA for detecting mitochondrial autophagy. Talanta 2025; 281:126885. [PMID: 39277929 DOI: 10.1016/j.talanta.2024.126885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/19/2024] [Accepted: 09/13/2024] [Indexed: 09/17/2024]
Abstract
Mitochondria are crucial powerhouses and central organelles for maintaining normal physiological activities in eukaryotic cells. The use of highly specific optical biosensors to monitor mitochondrial autophagy (mitophagy) is an important way for detecting mitochondrial abnormalities. Herein, we report a pH responsive G-quadruplex (G4) structure folded by the oligonucleotide named P24. P24 is composed of four GGCCTG repeating units, and the high guanine content allows it to form an antiparallel G4 topology at pH 4.5 (lysosomal pH). However, when pH increases to around 7.4 (mitochondrial pH), P24 further transforms into a double-stranded structure. Unlike most oligonucleotides that enter lysosomes, P24 highly targets mitochondria in live cells. These characteristics enable P24 to construct a pH responsive optical biosensor by linking a pair of fluorescence resonance energy transfer (FRET) fluorophores. The P24 based biosensor demonstrates reliable applications in detecting mitophagy in live cells.
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Affiliation(s)
- Dawei Yang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ranran Sun
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hongxia Sun
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Qian Li
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, China
| | - Hong Zhang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiufeng Zhang
- College of Chemistry Engineering, North China University of Science and Technology, Tangshan, China
| | - Lei Shi
- College of Chemistry Engineering, North China University of Science and Technology, Tangshan, China
| | - Li Yao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Yalin Tang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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10
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Al Amin M, Dehbia Z, Nafady MH, Zehravi M, Kumar KP, Haque MA, Baig MS, Farhana A, Khan SL, Afroz T, Koula D, Tutone M, Nainu F, Ahmad I, Emran TB. Flavonoids and Alzheimer’s disease: reviewing the evidence for neuroprotective potential. Mol Cell Biochem 2025; 480:43-73. [PMID: 38568359 DOI: 10.1007/s11010-023-04922-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/22/2023] [Indexed: 01/03/2025]
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11
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Huang KC, Gomes C, Shiga Y, Belforte N, VanderWall KB, Lavekar SS, Fligor CM, Harkin J, Hetzer SM, Patil SV, Di Polo A, Meyer JS. Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction. Acta Neuropathol Commun 2024; 12:164. [PMID: 39425218 PMCID: PMC11487784 DOI: 10.1186/s40478-024-01872-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024] Open
Abstract
The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) has led to numerous advances in the field of retinal research, with great potential for the use of hPSC-derived RGCs for studies of human retinal development, in vitro disease modeling, drug discovery, as well as their potential use for cell replacement therapeutics. Of all these possibilities, the use of hPSC-derived RGCs as a human-relevant platform for in vitro disease modeling has received the greatest attention, due to the translational relevance as well as the immediacy with which results may be obtained compared to more complex applications like cell replacement. While several studies to date have focused upon the use of hPSC-derived RGCs with genetic variants associated with glaucoma or other optic neuropathies, many of these have largely described cellular phenotypes with only limited advancement into exploring dysfunctional cellular pathways as a consequence of the disease-associated gene variants. Thus, to further advance this field of research, in the current study we leveraged an isogenic hPSC model with a glaucoma-associated mutation in the Optineurin (OPTN) protein, which plays a prominent role in autophagy. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs differentiated from hPSCs, and have further validated some of these findings in a mouse model of ocular hypertension. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs. Taken together, these results highlighted that autophagy disruption resulted in increased autophagic demand which was associated with downregulated signaling through mTORC1, contributing to the degeneration of RGCs.
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Affiliation(s)
- Kang-Chieh Huang
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Cátia Gomes
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yukihiro Shiga
- Department of Neuroscience, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Research Centre, Montreal, QC, Canada
| | - Nicolas Belforte
- Department of Neuroscience, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Research Centre, Montreal, QC, Canada
| | - Kirstin B VanderWall
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sailee S Lavekar
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Clarisse M Fligor
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jade Harkin
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Shelby M Hetzer
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Shruti V Patil
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Adriana Di Polo
- Department of Neuroscience, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Research Centre, Montreal, QC, Canada
| | - Jason S Meyer
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
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12
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Xiao X, Tang T, Bi M, Liu J, Liu M, Jiao Q, Chen X, Yan C, Du X, Jiang H. GHSR deficiency exacerbates Parkinson's disease pathology by impairing autophagy. Redox Biol 2024; 76:103322. [PMID: 39180981 PMCID: PMC11388265 DOI: 10.1016/j.redox.2024.103322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/18/2024] [Accepted: 08/18/2024] [Indexed: 08/27/2024] Open
Abstract
In Parkinson's disease (PD), exogenous ghrelin protects dopaminergic neurons through its receptor, growth hormone secretagogue receptor (GHSR). However, in contrast to the strikingly low levels of ghrelin, GHSR is highly expressed in the substantia nigra (SN). What role does GHSR play in dopaminergic neurons is unknown. In this study, using GHSR knockout mice (Ghsr-/- mice) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, we found that GHSR deletion aggravated dopaminergic neurons degeneration, and the expression and activity of GHSR were significantly reduced in PD. Furthermore, we explored the potential mechanism that GHSR deficiency aggregated PD-related neurodegeneration. We showed that DEPTOR, a subunit of mTORC1, was overexpressed in Ghsr-/- mice, positively regulating autophagy and enhancing autophagy initiation. The expression of lysosomal markers was abnormal, implying lysosomal dysfunction. As a result, the damaged mitochondria could not be effectively eliminated, which ultimately exacerbated the injury of nigral dopaminergic neurons. In particular, we demonstrated that DEPTOR could be transcriptionally regulated by KLF4. Specific knockdown of KLF4 in dopaminergic neurons effectively alleviated neurodegeneration in Ghsr-/- mice. In summary, our results suggested that endogenous GHSR deletion-compromised autophagy by impairing lysosomal function, is a key contributor to PD, which provided ideas for therapeutic approaches involving the manipulation of GHSR.
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Affiliation(s)
- Xue Xiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Tingting Tang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Mingxia Bi
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Jing Liu
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Mengru Liu
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xi Chen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Chunling Yan
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China; Qingdao Key Laboratory of Neurorehabilitation, University of Health and Rehabilitation Sciences, Qingdao, 266113, China.
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13
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Riordan R, Saxton A, McMillan PJ, Kow RL, Liachko NF, Kraemer BC. TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.11.598478. [PMID: 38915598 PMCID: PMC11195232 DOI: 10.1101/2024.06.11.598478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for a diverse range of neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD) with progranulin (PGRN) haplo-insufficiency, although the molecular mechanisms involved are not yet understood. Through advances in cryo-electron microscopy (cryo-EM), homotypic aggregates of the C-Terminal domain of TMEM106B (TMEM CT) were discovered as a previously unidentified cytosolic proteinopathy in the brains of FTLD, Alzheimer's disease, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) patients. While it remains unknown what role TMEM CT aggregation plays in neuronal loss, its presence across a range of aging related dementia disorders indicates involvement in multi-proteinopathy driven neurodegeneration. To determine the TMEM CT aggregation propensity and neurodegenerative potential, we characterized a novel transgenic C. elegans model expressing the human TMEM CT fragment constituting the fibrillar core seen in FTLD cases. We found that pan-neuronal expression of human TMEM CT in C. elegans causes neuronal dysfunction as evidenced by behavioral analysis. Cytosolic aggregation of TMEM CT proteins accompanied the behavioral dysfunction driving neurodegeneration, as illustrated by loss of GABAergic neurons. To investigate the molecular mechanisms driving TMEM106B proteinopathy, we explored the impact of PGRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressing C. elegans with loss of pgrn-1, the C. elegans ortholog of human PGRN. Neither full nor partial loss of pgrn-1 altered the motor phenotype of our TMEM CT model suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. We also tested the ability of genetic suppressors of tauopathy to rescue TMEM CT pathology. We found that genetic knockout of spop-1, sut-2, and sut-6 resulted in weak to no rescue of proteinopathy phenotypes, indicating that the mechanistic drivers of TMEM106B proteinopathy may be distinct from tauopathy. Taken together, our data demonstrate that TMEM CT aggregation can kill neurons. Further, expression of TMEM CT in C. elegans neurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease.
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Affiliation(s)
- Ruben Riordan
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA
| | - Aleen Saxton
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Pamela J. McMillan
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA
| | - Rebecca L Kow
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA
| | - Nicole F. Liachko
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA
| | - Brian C. Kraemer
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington 98195, USA
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14
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Vongthip W, Nilkhet S, Boonruang K, Sukprasansap M, Tencomnao T, Baek SJ. Neuroprotective mechanisms of luteolin in glutamate-induced oxidative stress and autophagy-mediated neuronal cell death. Sci Rep 2024; 14:7707. [PMID: 38565590 PMCID: PMC10987666 DOI: 10.1038/s41598-024-57824-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Neurodegenerative diseases, characterized by progressive neuronal dysfunction and loss, pose significant health challenges. Glutamate accumulation contributes to neuronal cell death in diseases such as Alzheimer's disease. This study investigates the neuroprotective potential of Albizia lebbeck leaf extract and its major constituent, luteolin, against glutamate-induced hippocampal neuronal cell death. Glutamate-treated HT-22 cells exhibited reduced viability, altered morphology, increased ROS, and apoptosis, which were attenuated by pre-treatment with A. lebbeck extract and luteolin. Luteolin also restored mitochondrial function, decreased mitochondrial superoxide, and preserved mitochondrial morphology. Notably, we first found that luteolin inhibited the excessive process of mitophagy via the inactivation of BNIP3L/NIX and inhibited lysosomal activity. Our study suggests that glutamate-induced autophagy-mediated cell death is attenuated by luteolin via activation of mTORC1. These findings highlight the potential of A. lebbeck as a neuroprotective agent, with luteolin inhibiting glutamate-induced neurotoxicity by regulating autophagy and mitochondrial dynamics.
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Affiliation(s)
- Wudtipong Vongthip
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Program in Clinical Biochemistry and Molecular Medicine, Chulalongkorn University, 10330, Bangkok, Thailand
- Laboratory of Signal Transduction, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
| | - Sunita Nilkhet
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Program in Clinical Biochemistry and Molecular Medicine, Chulalongkorn University, 10330, Bangkok, Thailand
- Laboratory of Signal Transduction, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
| | - Kanokkan Boonruang
- Laboratory of Signal Transduction, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
| | - Monruedee Sukprasansap
- Food Toxicology Unit, Institute of Nutrition, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Tewin Tencomnao
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Seung Joon Baek
- Laboratory of Signal Transduction, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
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15
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Alberti C, Rizzo F, Anastasia A, Comi G, Corti S, Abati E. Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives. Neurobiol Dis 2024; 193:106467. [PMID: 38452947 DOI: 10.1016/j.nbd.2024.106467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024] Open
Abstract
Mutations in the gene encoding MFN2 have been identified as associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a neurological disorder characterized by a broad clinical phenotype involving the entire nervous system. MFN2, a dynamin-like GTPase protein located on the outer mitochondrial membrane, is well-known for its involvement in mitochondrial fusion. Numerous studies have demonstrated its participation in a network crucial for various other mitochondrial functions, including mitophagy, axonal transport, and its controversial role in endoplasmic reticulum (ER)-mitochondria contacts. Considerable progress has been made in the last three decades in elucidating the disease pathogenesis, aided by the generation of animal and cellular models that have been instrumental in studying disease physiology. A review of the literature reveals that, up to now, no definitive pharmacological treatment for any CMT2A variant has been established; nonetheless, recent years have witnessed substantial progress. Many treatment approaches, especially concerning molecular therapy, such as histone deacetylase inhibitors, peptide therapy to increase mitochondrial fusion, the new therapeutic strategies based on MF1/MF2 balance, and SARM1 inhibitors, are currently in preclinical testing. The literature on gene silencing and gene replacement therapies is still limited, except for a recent study by Rizzo et al.(Rizzo et al., 2023), which recently first achieved encouraging results in in vitro and in vivo models of the disease. The near-future goal for these promising therapies is to progress to the stage of clinical translation.
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Affiliation(s)
- Claudia Alberti
- Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy
| | - Federica Rizzo
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Alessia Anastasia
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giacomo Comi
- Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy; Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefania Corti
- Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy; Neuromuscular and Rare Diseases Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elena Abati
- Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy; Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
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16
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Zhong MZ, Peng T, Duarte ML, Wang M, Cai D. Updates on mouse models of Alzheimer's disease. Mol Neurodegener 2024; 19:23. [PMID: 38462606 PMCID: PMC10926682 DOI: 10.1186/s13024-024-00712-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 02/14/2024] [Indexed: 03/12/2024] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease in the United States (US). Animal models, specifically mouse models have been developed to better elucidate disease mechanisms and test therapeutic strategies for AD. A large portion of effort in the field was focused on developing transgenic (Tg) mouse models through over-expression of genetic mutations associated with familial AD (FAD) patients. Newer generations of mouse models through knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, have been developed for both familial and sporadic AD risk genes with the hope to more accurately model proteinopathies without over-expression of human AD genes in mouse brains. In this review, we summarized the phenotypes of a few commonly used as well as newly developed mouse models in translational research laboratories including the presence or absence of key pathological features of AD such as amyloid and tau pathology, synaptic and neuronal degeneration as well as cognitive and behavior deficits. In addition, advantages and limitations of these AD mouse models have been elaborated along with discussions of any sex-specific features. More importantly, the omics data from available AD mouse models have been analyzed to categorize molecular signatures of each model reminiscent of human AD brain changes, with the hope to guide future selection of most suitable models for specific research questions to be addressed in the AD field.
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Affiliation(s)
- Michael Z Zhong
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Biology, College of Arts and Science, Boston University, Boston, MA, 02215, USA
| | - Thomas Peng
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Science Research Program, Scarsdale High School, New York, NY, 10583, USA
| | - Mariana Lemos Duarte
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Research & Development, James J Peters VA Medical Center, Bronx, NY, 10468, USA.
| | - Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
| | - Dongming Cai
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Research & Development, James J Peters VA Medical Center, Bronx, NY, 10468, USA.
- Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Neurology, N. Bud Grossman Center for Memory Research and Care, The University of Minnesota, Minneapolis, MN, 55455, USA.
- Geriatric Research Education & Clinical Center (GRECC), The Minneapolis VA Health Care System, Minneapolis, MN, 55417, USA.
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17
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Almeida MF, Farizatto KLG, Almeida RS, Bahr BA. Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies. Ageing Res Rev 2024; 93:102162. [PMID: 38070831 DOI: 10.1016/j.arr.2023.102162] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 10/31/2023] [Accepted: 12/05/2023] [Indexed: 12/21/2023]
Abstract
Unhealthy lifestyle choices, poor diet, and aging can have negative influences on cognition, gradually increasing the risk for mild cognitive impairment (MCI) and the continuum comprising early dementia. Aging is the greatest risk factor for age-related dementias such as Alzheimer's disease, and the aging process is known to be influenced by life events that can positively or negatively affect age-related diseases. Remarkably, life experiences that make the brain vulnerable to dementia, such as seizure episodes, neurotoxin exposures, metabolic disorders, and trauma-inducing events (e.g. traumatic injuries or mild neurotrauma from a fall or blast exposure), have been associated with negative effects on proteostasis and synaptic integrity. Functional compromise of the autophagy-lysosomal pathway, a major contributor to proteostasis, has been implicated in Alzheimer's disease, Parkinson's disease, obesity-related pathology, Huntington's disease, as well as in synaptic degeneration which is the best correlate of cognitive decline. Correspondingly, pharmacological and non-pharmacological strategies that positively modulate lysosomal proteases are recognized as synaptoprotective through degradative clearance of pathogenic proteins. Here, we discuss life-associated vulnerabilities that influence key hallmarks of brain aging and the increased burden of age-related dementias. Additionally, we discuss exercise and diet among the lifestyle strategies that regulate proteostasis as well as synaptic integrity, leading to evident prevention of cognitive deficits during brain aging in pre-clinical models.
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Affiliation(s)
- Michael F Almeida
- Biotechnology Research and Training Center, University of North Carolina - Pembroke, Pembroke, NC 28372, USA; Department of Biology, University of North Carolina - Pembroke, Pembroke, NC 28372, USA; Department of Biology & Marine Biology, and the Integrative, Comparative & Marine Biology Program, University of North Carolina - Wilmington, Wilmington, NC 28409, USA
| | - Karen L G Farizatto
- Biotechnology Research and Training Center, University of North Carolina - Pembroke, Pembroke, NC 28372, USA
| | - Renato S Almeida
- Department of Biosciences, University of Taubate, Taubate, SP 12020-270, Brazil
| | - Ben A Bahr
- Biotechnology Research and Training Center, University of North Carolina - Pembroke, Pembroke, NC 28372, USA; Department of Biology, University of North Carolina - Pembroke, Pembroke, NC 28372, USA.
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18
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Li X, Chen S, Zheng G, Yang Y, Yin N, Niu X, Yao L, Lv P. Atorvastatin Calcium Ameliorates Cognitive Deficits Through the AMPK/Mtor Pathway in Rats with Vascular Dementia. Comb Chem High Throughput Screen 2024; 27:148-156. [PMID: 37282650 DOI: 10.2174/1386207326666230606114448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/22/2023] [Accepted: 05/25/2023] [Indexed: 06/08/2023]
Abstract
AIM In this study, the protective effects of atorvastatin calcium (AC) on nerve cells and cognitive improvement in vivo and in vitro were investigated by establishing cell models and vascular dementia (VD) rat models. BACKGROUND VD is a neurodegenerative disease characterized by cognitive deficits caused by chronic cerebral hypoperfusion. AC has been studied for its potential to cure VD but its efficacy and underlying mechanism are still unclear. OBJECTIVE The mechanism of action of AC on cognitive deficits in the early stages of VD is unclear. Here, the 2-vessel occlusion (2-VO) model in vivo and the hypoxia/reoxygenation (H/R) cell model in vitro was established to investigate the function of AC in VD. METHODS The spatial learning and memory abilities of rats were detected by the Morris method. The IL-6, tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) in cell supernatant was tested by ELISA kits. After behavioural experiments, rats were anaesthetized and sacrificed, and their brains were extracted. One part was immediately fixed in 4% paraformaldehyde for H&E, Nissl, and immunohistochemical analyses, and the other was stored in liquid nitrogen. All data were shown as mean ± SD. Statistical comparison between the two groups was performed by Student's t-test. A two-way ANOVA test using GraphPad Prism 7 was applied for escape latency analysis and the swimming speed test. The difference was considered statistically significant at p < 0.05. RESULTS AC decreased apoptosis, increased autophagy, and alleviated oxidative stress in primary hippocampal neurons. AC regulated autophagy-related proteins in vitro by western blotting. VD mice improved cognitively in the Morris water maze. Spatial probing tests showed that VD animals administered AC had considerably longer swimming times to the platform than VD rats. H&E and Nissl staining showed that AC reduces neuronal damage in VD rats. Western blot and qRT-PCR indicated that AC in VD rats inhibited Bax and promoted LC3-II, Beclin-1, and Bcl-2 in the hippocampus region. AC also improves cognition via the AMPK/mTOR pathway. CONCLUSION This study found that AC may relieve learning and memory deficits as well as neuronal damage in VD rats by changing the expression of apoptosis/autophagy-related genes and activating the AMPK/mTOR signalling pathway in neurons.
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Affiliation(s)
- Xiuqin Li
- Department of Neurology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China
- Department of Geriatrics, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Shaopeng Chen
- Department of Preventive Health, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Guiming Zheng
- Department of Rheumatology and Immunology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Yanyan Yang
- Department of Gynecology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Nan Yin
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Xiaoli Niu
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Lixia Yao
- Department of Geriatrics, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Peiyuan Lv
- Department of Neurology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
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19
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Agarwal R, Iezhitsa I. Genetic rodent models of glaucoma in representing disease phenotype and insights into the pathogenesis. Mol Aspects Med 2023; 94:101228. [PMID: 38016252 DOI: 10.1016/j.mam.2023.101228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/31/2023] [Accepted: 11/11/2023] [Indexed: 11/30/2023]
Abstract
Genetic rodent models are widely used in glaucoma related research. With vast amount of information revealed by human studies about genetic correlations with glaucoma, use of these models is relevant and required. In this review, we discuss the glaucoma endophenotypes and importance of their representation in an experimental animal model. Mice and rats are the most popular animal species used as genetic models due to ease of genetic manipulations in these animal species as well as the availability of their genomic information. With technological advances, induction of glaucoma related genetic mutations commonly observed in human is possible to achieve in rodents in a desirable manner. This approach helps to study the pathobiology of the disease process with the background of genetic abnormalities, reveals potential therapeutic targets and gives an opportunity to test newer therapeutic options. Various genetic manipulation leading to appearance of human relevant endophenotypes in rodents indicate their relevance in glaucoma pathology and the utility of these rodent models for exploring various aspects of the disease related to targeted mutation. The molecular pathways involved in the pathophysiology of glaucoma leading to elevated intraocular pressure and the disease hallmark, apoptosis of retinal ganglion cells and optic nerve degeneration, have been extensively explored in genetic rodent models. In this review, we discuss the consequences of various genetic manipulations based on the primary site of pathology in the anterior or the posterior segment. We discuss how these genetic manipulations produce features in rodents that can be considered a close representation of disease phenotype in human. We also highlight several molecular mechanisms revealed by using genetic rodent models of glaucoma including those involved in increased aqueous outflow resistance, loss of retinal ganglion cells and optic neuropathy. Lastly, we discuss the limitations of the use of genetic rodent models in glaucoma related research.
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Affiliation(s)
- Renu Agarwal
- School of Medicine, International Medical University, Malaysia.
| | - Igor Iezhitsa
- School of Medicine, International Medical University, Malaysia
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20
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Holt AG, Davies AM. The prevalence of dementia in humans could be the result of a functional adaptation. Comput Biol Chem 2023; 106:107939. [PMID: 37598466 DOI: 10.1016/j.compbiolchem.2023.107939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/31/2023] [Accepted: 08/07/2023] [Indexed: 08/22/2023]
Abstract
In this paper we propose that high copy number of the mitochondrial genome in neurons is a functional adaptation. We simulated the proliferation of deletion mutants of the human mitochondrial genome in a virtual mitochondrion and recorded the cell loss rates due to deletions overwhelming the wild-type. Our results showed that cell loss increased with mtDNA copy number. Given that neuron loss equates to cognitive dysfunction, it would seem counterintuitive that there would be a selective pressure for high copy number over low. However, for a low copy number, the onset of cognitive decline, while mild, started early in life. Whereas, for high copy number, it did not start until middle age but progressed rapidly. There could have been an advantage to high copy number in the brain if it delayed the onset of cognitive decline until after reproductive age. The prevalence of dementia in our aged population is a consequence of this functional adaptation.
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21
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Kaur B, Sharma PK, Chatterjee B, Bissa B, Nattarayan V, Ramasamy S, Bhat A, Lal M, Samaddar S, Banerjee S, Roy SS. Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity. Cell Commun Signal 2023; 21:258. [PMID: 37749555 PMCID: PMC10518934 DOI: 10.1186/s12964-023-01288-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/19/2023] [Indexed: 09/27/2023] Open
Abstract
Homocysteine (Hcy), produced physiologically in all cells, is an intermediate metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) resulting from an in-born error of metabolism that leads to accumulation of high levels of Hcy, is associated with vascular damage, neurodegeneration and cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced neurotoxicity associated with mitochondrial dysfunction, fragmentation and apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced proteotoxicity leading to ER stress. We show this sustained proteotoxicity originates from the perturbation of upstream autophagic pathways through an aberrant activation of mTOR and that protetoxic stress act as a feedforward cues to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also rescue neuronal lethality by activation of autophagy and thereby reducing proteotoxicity and ER stress. Our findings pave the way to devise new strategies for the treatment of neural and cognitive pathologies reported in HHcy, by either activation of upstream autophagy or by suppression of downstream ER stress. Video Abstract.
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Affiliation(s)
- Bhavneet Kaur
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
- Academy of Scientific & Innovative Research, Ghaziabad, 201002, India
| | - Pradeep Kumar Sharma
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
- Academy of Scientific & Innovative Research, Ghaziabad, 201002, India
- CSIR-Indian Institute of Toxicology Research, Lucknow, India
| | - Barun Chatterjee
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
- Academy of Scientific & Innovative Research, Ghaziabad, 201002, India
| | - Bhawana Bissa
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
- Present address: Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| | - Vasugi Nattarayan
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
| | - Soundhar Ramasamy
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
- Academy of Scientific & Innovative Research, Ghaziabad, 201002, India
| | - Ajay Bhat
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
- Academy of Scientific & Innovative Research, Ghaziabad, 201002, India
| | - Megha Lal
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India
- Academy of Scientific & Innovative Research, Ghaziabad, 201002, India
| | | | | | - Soumya Sinha Roy
- CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India.
- Academy of Scientific & Innovative Research, Ghaziabad, 201002, India.
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22
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Im E, Jiang Y, Stavrides PH, Darji S, Erdjument-Bromage H, Neubert TA, Choi JY, Wegiel J, Lee JH, Nixon RA. Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr 682-phosphorylated APP βCTF. SCIENCE ADVANCES 2023; 9:eadg1925. [PMID: 37494443 PMCID: PMC10371027 DOI: 10.1126/sciadv.adg1925] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 06/23/2023] [Indexed: 07/28/2023]
Abstract
Lysosome dysfunction arises early and propels Alzheimer's disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) to disrupt lysosomal vacuolar (H+)-adenosine triphosphatase (v-ATPase) and acidification. In human DS fibroblasts, the phosphorylated 682YENPTY internalization motif of APP-βCTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-βCTF Tyr682 phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-βCTF Tyr682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF. Elevated APP-βCTF Tyr682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer previously unknown insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.
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Affiliation(s)
- Eunju Im
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ying Jiang
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Philip H. Stavrides
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
| | - Sandipkumar Darji
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
| | - Hediye Erdjument-Bromage
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Thomas A. Neubert
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Jun Yong Choi
- Department of Chemistry and Biochemistry, Queens College, Queens, NY 11367, USA
- Ph.D. Programs in Chemistry and Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - Jerzy Wegiel
- Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA
| | - Ju-Hyun Lee
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ralph A. Nixon
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA
- NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA
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23
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Magalhães HIR, Machado FA, Souza RF, Caetano MAF, Figliuolo VR, Coutinho-Silva R, Castelucci P. Study of the roles of caspase-3 and nuclear factor kappa B in myenteric neurons in a P2X7 receptor knockout mouse model of ulcerative colitis. World J Gastroenterol 2023; 29:3440-3468. [PMID: 37389242 PMCID: PMC10303518 DOI: 10.3748/wjg.v29.i22.3440] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/25/2023] [Accepted: 05/12/2023] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases (IBDs) and that the P2X7 receptor triggers neuronal death. However, the mechanism by which enteric neurons are lost in IBDs is unknown. AIM To study the role of the caspase-3 and nuclear factor kappa B (NF-κB) pathways in myenteric neurons in a P2X7 receptor knockout (KO) mouse model of IBDs. METHODS Forty male wild-type (WT) C57BL/6 and P2X7 receptor KO mice were euthanized 24 h or 4 d after colitis induction by 2,4,6-trinitrobenzene sulfonic acid (colitis group). Mice in the sham groups were injected with vehicle. The mice were divided into eight groups (n = 5): The WT sham 24 h and 4 d groups, the WT colitis 24 h and 4 d groups, the KO sham 24 h and 4 d groups, and the KO colitis 24 h and 4 d groups. The disease activity index (DAI) was analyzed, the distal colon was collected for immunohistochemistry analyses, and immunofluorescence was performed to identify neurons immunoreactive (ir) for calretinin, P2X7 receptor, cleaved caspase-3, total caspase-3, phospho-NF-κB, and total NF-κB. We analyzed the number of calretinin-ir and P2X7 receptor-ir neurons per ganglion, the neuronal profile area (µm²), and corrected total cell fluorescence (CTCF). RESULTS Cells double labeled for calretinin and P2X7 receptor, cleaved caspase-3, total caspase-3, phospho-NF-κB, or total NF-κB were observed in the WT colitis 24 h and 4 d groups. The number of calretinin-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (2.10 ± 0.13 vs 3.33 ± 0.17, P < 0.001; 2.92 ± 0.12 vs 3.70 ± 0.11, P < 0.05), but was not significantly different between the KO groups. The calretinin-ir neuronal profile area was increased in the WT colitis 24 h group compared to the WT sham 24 h group (312.60 ± 7.85 vs 278.41 ± 6.65, P < 0.05), and the nuclear profile area was decreased in the WT colitis 4 d group compared to the WT sham 4 d group (104.63 ± 2.49 vs 117.41 ± 1.14, P < 0.01). The number of P2X7 receptor-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (19.49 ± 0.35 vs 22.21 ± 0.18, P < 0.001; 20.35 ± 0.14 vs 22.75 ± 0.51, P < 0.001), and no P2X7 receptor-ir neurons were observed in the KO groups. Myenteric neurons showed ultrastructural changes in the WT colitis 24 h and 4 d groups and in the KO colitis 24 h group. The cleaved caspase-3 CTCF was increased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (485949 ± 14140 vs 371371 ± 16426, P < 0.001; 480381 ± 11336 vs 378365 ± 4053, P < 0.001), but was not significantly different between the KO groups. The total caspase-3 CTCF, phospho-NF-κB CTCF, and total NF-κB CTCF were not significantly different among the groups. The DAI was recovered in the KO groups. Furthermore, we demonstrated that the absence of the P2X7 receptor attenuated inflammatory infiltration, tissue damage, collagen deposition, and the decrease in the number of goblet cells in the distal colon. CONCLUSION Ulcerative colitis affects myenteric neurons in WT mice but has a weaker effect in P2X7 receptor KO mice, and neuronal death may be associated with P2X7 receptor-mediated caspase-3 activation. The P2X7 receptor can be a therapeutic target for IBDs.
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Affiliation(s)
| | | | | | | | - Vanessa Ribeiro Figliuolo
- Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Robson Coutinho-Silva
- Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
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24
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Wu M, Chen Z, Jiang M, Bao B, Li D, Yin X, Wang X, Liu D, Zhu LQ. Friend or foe: role of pathological tau in neuronal death. Mol Psychiatry 2023; 28:2215-2227. [PMID: 36918705 DOI: 10.1038/s41380-023-02024-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/25/2023] [Accepted: 02/28/2023] [Indexed: 03/16/2023]
Abstract
Neuronal death is one of the most common pathological hallmarks of diverse neurological diseases, which manifest varying degrees of cognitive or motor dysfunction. Neuronal death can be classified into multiple forms with complicated and unique regulatory signaling pathways. Tau is a key microtubule-associated protein that is predominantly expressed in neurons to stabilize microtubules under physiological conditions. In contrast, pathological tau always detaches from microtubules and is implicated in a series of neurological disorders that are characterized by irreversible neuronal death, such as necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent neuronal death and phagocytosis by microglia. However, recent studies have also revealed that pathological tau can facilitate neuron escape from acute apoptosis, delay necroptosis through its action on granulovacuolar degeneration bodies (GVBs), and facilitate iron export from neurons to block ferroptosis. In this review, we briefly describe the current understanding of how pathological tau exerts dual effects on neuronal death by acting as a double-edged sword in different neurological diseases. We propose that elucidating the mechanism by which pathological tau affects neuronal death is critical for exploring novel and precise therapeutic strategies for neurological disorders.
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Affiliation(s)
- Moxin Wu
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China
| | - Zhiying Chen
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China
| | - Min Jiang
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China
| | - Bing Bao
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China
| | - Dongling Li
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China
| | - Xiaoping Yin
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China.
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China.
| | - Xueren Wang
- Department of Anesthesiology, Shanxi Bethune Hospital, Taiyuan, 030032, China.
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Dan Liu
- Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Ling-Qiang Zhu
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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25
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Ryu IS, Kim DH, Cho HJ, Ryu JH. The role of microRNA-485 in neurodegenerative diseases. Rev Neurosci 2023; 34:49-62. [PMID: 35793556 DOI: 10.1515/revneuro-2022-0039] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/19/2022] [Indexed: 01/11/2023]
Abstract
Neurodegenerative diseases (NDDs) are age-related disorders characterized by progressive neurodegeneration and neuronal cell loss in the central nervous system. Neuropathological conditions such as the accumulation of misfolded proteins can cause neuroinflammation, apoptosis, and synaptic dysfunction in the brain, leading to the development of NDDs including Alzheimer's disease (AD) and Parkinson's disease (PD). MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene expression post-transcriptionally via RNA interference. Recently, some studies have reported that some miRNAs play an important role in the development of NDDs by regulating target gene expression. MiRNA-485 (miR-485) is a highly conserved brain-enriched miRNA. Accumulating clinical reports suggest that dysregulated miR-485 may be involved in the pathogenesis of AD and PD. Emerging studies have also shown that miR-485 plays a novel role in the regulation of neuroinflammation, apoptosis, and synaptic function in the pathogenesis of NDDs. In this review, we introduce the biological characteristics of miR-485, provide clinical evidence of the dysregulated miR-485 in NDDs, novel roles of miR-485 in neuropathological events, and discuss the potential of targeting miR-485 as a diagnostic and therapeutic marker for NDDs.
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Affiliation(s)
- In Soo Ryu
- Biorchestra Co. Ltd., 17, Techno 4-ro, Yuseong-gu, Daejeon 34013, South Korea
| | - Dae Hoon Kim
- Biorchestra Co. Ltd., 17, Techno 4-ro, Yuseong-gu, Daejeon 34013, South Korea
| | - Hyun-Jeong Cho
- Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, 158, Gwanjeodong-ro, Seo-gu, Daejeon 35365, South Korea
| | - Jin-Hyeob Ryu
- Biorchestra Co. Ltd., 17, Techno 4-ro, Yuseong-gu, Daejeon 34013, South Korea.,Biorchestra Co. Ltd., 245 Main St, Cambridge, MA 02142, USA
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26
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Huang KC, Gomes C, Shiga Y, Belforte N, VanderWall KB, Lavekar SS, Fligor CM, Harkin J, Di Polo A, Meyer JS. Autophagy disruption reduces mTORC1 activation leading to retinal ganglion cell neurodegeneration associated with glaucoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.04.522687. [PMID: 36711831 PMCID: PMC9881969 DOI: 10.1101/2023.01.04.522687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Autophagy dysfunction has been associated with several neurodegenerative diseases including glaucoma, characterized by the degeneration of retinal ganglion cells (RGCs). However, the mechanisms by which autophagy dysfunction promotes RGC damage remain unclear. Here, we hypothesized that perturbation of the autophagy pathway results in increased autophagic demand, thereby downregulating signaling through mammalian target of rapamycin complex 1 (mTORC1), a negative regulator of autophagy, contributing to the degeneration of RGCs. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor adenosine monophosphate-activated protein kinase (AMPK), along with subsequent neurodegeneration in RGCs differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated variant of Optineurin (OPTN-E50K). Similarly, the microbead occlusion model of glaucoma resulting in ocular hypertension also exhibited autophagy disruption and mTORC1 downregulation. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN-E50K RGCs. Taken together, these results highlight an important balance between autophagy and mTORC1 signaling essential for RGC homeostasis, while disruption to these pathways contributes to neurodegenerative features in glaucoma, providing a potential therapeutic target to prevent neurodegeneration.
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Affiliation(s)
- Kang-Chieh Huang
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis IN USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis IN USA
| | - Cátia Gomes
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis IN USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN USA
| | - Yukihiro Shiga
- Department of Neuroscience, University of Montreal, Montreal, Quebec, Canada
- University of Montreal Hospital Research Centre, Montreal, Quebec, Canada
| | - Nicolas Belforte
- Department of Neuroscience, University of Montreal, Montreal, Quebec, Canada
- University of Montreal Hospital Research Centre, Montreal, Quebec, Canada
| | - Kirstin B. VanderWall
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis IN USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis IN USA
| | - Sailee S. Lavekar
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis IN USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis IN USA
| | - Clarisse M. Fligor
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis IN USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis IN USA
| | - Jade Harkin
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis IN USA
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis IN USA
| | - Adriana Di Polo
- Department of Neuroscience, University of Montreal, Montreal, Quebec, Canada
- University of Montreal Hospital Research Centre, Montreal, Quebec, Canada
| | - Jason S. Meyer
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis IN USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN USA
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis IN USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis IN USA
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27
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Lee Y, Miller MR, Fernandez MA, Berg EL, Prada AM, Ouyang Q, Schmidt M, Silverman JL, Young-Pearse TL, Morrow EM. Early lysosome defects precede neurodegeneration with amyloid-β and tau aggregation in NHE6-null rat brain. Brain 2022; 145:3187-3202. [PMID: 34928329 PMCID: PMC10147331 DOI: 10.1093/brain/awab467] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 10/25/2021] [Accepted: 11/24/2021] [Indexed: 11/12/2022] Open
Abstract
Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome in males. Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-β levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-β and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-β. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-β and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-β and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-β and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-β and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's disease and related dementias.
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Affiliation(s)
- YouJin Lee
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
- Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University, Providence, RI 02912, USA
| | - Morgan R Miller
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
- Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University, Providence, RI 02912, USA
| | - Marty A Fernandez
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Elizabeth L Berg
- MIND Institute and Department of Psychiatry and Behavioural Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Adriana M Prada
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
- Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University, Providence, RI 02912, USA
| | - Qing Ouyang
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
- Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University, Providence, RI 02912, USA
| | - Michael Schmidt
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
- Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University, Providence, RI 02912, USA
| | - Jill L Silverman
- MIND Institute and Department of Psychiatry and Behavioural Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Tracy L Young-Pearse
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Eric M Morrow
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
- Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University, Providence, RI 02912, USA
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28
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Changotra H, Kaur S, Yadav SS, Gupta GL, Parkash J, Duseja A. ATG5: A central autophagy regulator implicated in various human diseases. Cell Biochem Funct 2022; 40:650-667. [PMID: 36062813 DOI: 10.1002/cbf.3740] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/16/2022] [Accepted: 08/19/2022] [Indexed: 11/07/2022]
Abstract
Autophagy, an intracellular conserved degradative process, plays a central role in the renewal/recycling of a cell to maintain the homeostasis of nutrients and energy within the cell. ATG5, a key component of autophagy, regulates the formation of the autophagosome, a hallmark of autophagy. ATG5 binds with ATG12 and ATG16L1 resulting in E3 like ligase complex, which is necessary for autophagosome expansion. Available data suggest that ATG5 is indispensable for autophagy and has an imperative role in several essential biological processes. Moreover, ATG5 has also been demonstrated to possess autophagy-independent functions that magnify its significance and therapeutic potential. ATG5 interacts with various molecules for the execution of different processes implicated during physiological and pathological conditions. Furthermore, ATG5 genetic variants are associated with various ailments. This review discusses various autophagy-dependent and autophagy-independent roles of ATG5, highlights its various deleterious genetic variants reported until now, and various studies supporting it as a potential drug target.
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Affiliation(s)
- Harish Changotra
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Sargeet Kaur
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Suresh Singh Yadav
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Girdhari Lal Gupta
- Department of Pharmacology, School of Pharmacy and Technology Management, SVKM'S NMIMS, Shirpur, Maharashtra, India
| | - Jyoti Parkash
- Department of Zoology, School of Biological Sciences, Central University Punjab, Ghudda, Bathinda, Punjab, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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29
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Liu T, Zhu W, Zhang X, He C, Liu X, Xin Q, Chen K, Wang H. Recent Advances in Cell and Functional Biomaterial Treatment for Spinal Cord Injury. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5079153. [PMID: 35978649 PMCID: PMC9377911 DOI: 10.1155/2022/5079153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/17/2022] [Accepted: 07/25/2022] [Indexed: 12/17/2022]
Abstract
Spinal cord injury (SCI) is a devastating central nervous system disease caused by accidental events, resulting in loss of sensory and motor function. Considering the multiple effects of primary and secondary injuries after spinal cord injury, including oxidative stress, tissue apoptosis, inflammatory response, and neuronal autophagy, it is crucial to understand the underlying pathophysiological mechanisms, local microenvironment changes, and neural tissue functional recovery for preparing novel treatment strategies. Treatment based on cell transplantation has become the forefront of spinal cord injury therapy. The transplanted cells provide physical and nutritional support for the damaged tissue. At the same time, the implantation of biomaterials with specific biological functions at the site of the SCI has also been proved to improve the local inhibitory microenvironment and promote axonal regeneration, etc. The combined transplantation of cells and functional biomaterials for SCI treatment can result in greater neuroprotective and regenerative effects by regulating cell differentiation, enhancing cell survival, and providing physical and directional support for axon regeneration and neural circuit remodeling. This article reviews the pathophysiology of the spinal cord, changes in the microenvironment after injury, and the mechanisms and strategies for spinal cord regeneration and repair. The article will focus on summarizing and discussing the latest intervention models based on cell and functional biomaterial transplantation and the latest progress in combinational therapies in SCI repair. Finally, we propose the future prospects and challenges of current treatment regimens for SCI repair, to provide references for scientists and clinicians to seek better SCI repair strategies in the future.
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Affiliation(s)
- Tianyi Liu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Wenhao Zhu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Xiaoyu Zhang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Chuan He
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Xiaolong Liu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Qiang Xin
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Kexin Chen
- Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, China
| | - Haifeng Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
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30
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Panda SP, Dhurandhar Y, Agrawal M. The interplay of epilepsy with impaired mitophagy and autophagy linked dementia (MAD): A review of therapeutic approaches. Mitochondrion 2022; 66:27-37. [PMID: 35842181 DOI: 10.1016/j.mito.2022.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/21/2022] [Accepted: 07/10/2022] [Indexed: 12/28/2022]
Abstract
The duration and, age of dementia have been linked to a higher risk of seizures. The exact mechanism that drives epileptogenesis in impaired mitophagy and autophagy linked dementia (MAD) is fully defined after reviewing the Scopus, Publon, and Pubmed databases. The epileptogenesis in patients with Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) is due to involvement of amyloid plaques (Aβ), phosphorylated tau (pTau), Parkin, NF-kB and NLRP3 inflammasome. Microglia, the prime protective and inflammatory cells in the brain exert crosstalk between mitophagy and inflammation. Several researchers believed that the inflammatory brain cells microglia could be a therapeutic target for the treatment of a MAD associated epilepsy. There are conventional antiepileptic drugs such as gabapentin, lamotrigine, phenytoin sodium, carbamazepine, oxcarbazepine, felbamate, lamotrigine, valproate sodium, and topiramate are prescribed by a psychiatrist to suppress seizure frequency. Also, the conventional drugs generate serious adverse effects and synergises dementia characteristics. The adverse effect of carbamazepine is neurotoxic and also, damages haemopoietic system and respiratory tract. The phenytoin treatment causes cerebellar defect and anemia. Dementia and epilepsy have a complicated relationship, thus targeting mitophagy for cure of epileptic dementia makes sense. Complementary and alternative medicine (CAM) is one of the rising strategies by many patients of the world, not only to suppress seizure frequency but also to mitigate dementia characteristics of patients. Therefore our present review focus on the interplay between epilepsy and MAD and their treatment with CAM approaches.
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Affiliation(s)
- Siva Prasad Panda
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
| | - Yogita Dhurandhar
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
| | - Mehak Agrawal
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
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31
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Potenza RL, Lodeserto P, Orienti I. Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule. Int J Mol Sci 2022; 23:ijms23137426. [PMID: 35806431 PMCID: PMC9266536 DOI: 10.3390/ijms23137426] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/30/2022] [Accepted: 07/02/2022] [Indexed: 02/05/2023] Open
Abstract
Recently, several chemotherapeutic drugs have been repositioned in neurological diseases, based on common biological backgrounds and the inverse comorbidity between cancer and neurodegenerative diseases. Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide, 4-HPR) is a synthetic derivative of all-trans-retinoic acid initially proposed in anticancer therapy for its antitumor effects combined with limited toxicity. Subsequently, fenretinide has been proposed for other diseases, for which it was not intentionally designed for, due to its ability to influence different biological pathways, providing a broad spectrum of pharmacological effects. Here, we review the most relevant preclinical and clinical findings from fenretinide and discuss its therapeutic role towards cancer and neurological diseases, highlighting the hormetic behavior of this pleiotropic molecule.
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Affiliation(s)
- Rosa Luisa Potenza
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy
- Correspondence: ; Tel.: +39-06-49902389
| | - Pietro Lodeserto
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40127 Bologna, Italy; (P.L.); (I.O.)
| | - Isabella Orienti
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40127 Bologna, Italy; (P.L.); (I.O.)
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32
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Li Q, Wang L, Ji D, Yu W, Zhang Y, Xiang Y, Zhou C, Wang L, Deng P, Pi H, Lu Y, Ma Q, He M, Zhang L, Yu Z, Deng A. Metformin attenuates cadmium-induced degeneration of spiral ganglion neuron via restoring autophagic flux in primary culture. J Inorg Biochem 2022; 234:111901. [PMID: 35716551 DOI: 10.1016/j.jinorgbio.2022.111901] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 10/18/2022]
Abstract
Cadmium (Cd), a common environmental and occupational toxicant, is an important risk factor for hearing loss. After exposure, Cd accumulates in the inner ear and induces spiral ganglion neuron (SGN) degeneration; however, the underlying mechanisms are poorly understood. Dysfunctional autophagy has been implicated in many neurodegenerative diseases, including Cd-induced neurotoxicity. Metformin has been validated to confer not only anti-hyperglycaemic but also neuroprotective effects. However, the relationship between autophagy dysfunction, SGN degeneration, and the effect of metformin on Cd-induced SGN neurotoxicity has not yet been established. In this study, we demonstrate that metformin notably attenuates Cd-evoked SGN degeneration by restoring impaired autophagy flux, as evidenced by the suppression of Cd-induced elevation of autophagy markers microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and autophagy substrate protein p62 in degenerated SGN. Blockage of autophagy flux by chloroquine abolished metformin-induced neuroprotection against Cd-induced neurotoxicity in SGN. The results of this study reveal that autophagy dysfunction is an important component of Cd-induced SGN degeneration, and metformin may be a potential protective agent for attenuating SGN degeneration following Cd exposure.
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Affiliation(s)
- Qian Li
- Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Liuqian Wang
- Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Di Ji
- Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wei Yu
- Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yan Zhang
- Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yanghong Xiang
- Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chao Zhou
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Liting Wang
- Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ping Deng
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Huifeng Pi
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yonghui Lu
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qinlong Ma
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Mindi He
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lei Zhang
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhengping Yu
- Department of Occupational Health, Army Medical University (Third Military Medical University), Chongqing, China
| | - Anchun Deng
- Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
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33
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Li M, Huang Y, Song S, Shuang S, Dong C. Piperazine-Based Mitochondria-Immobilized pH Fluorescent Probe for Imaging Endogenous ONOO – and Real-Time Tracking of Mitophagy. ACS APPLIED BIO MATERIALS 2022; 5:2777-2785. [DOI: 10.1021/acsabm.2c00213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Minglu Li
- College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, P. R. China
| | - Yue Huang
- College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, P. R. China
| | - Shengmei Song
- Institute of Environmental Science, Shanxi University, Taiyuan 030006, P. R. China
| | - Shaomin Shuang
- College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, P. R. China
| | - Chuan Dong
- Institute of Environmental Science, Shanxi University, Taiyuan 030006, P. R. China
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34
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Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis. Cell Discov 2022; 8:40. [PMID: 35504898 PMCID: PMC9065108 DOI: 10.1038/s41421-022-00390-6] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 02/16/2022] [Indexed: 11/08/2022] Open
Abstract
Ferroptosis is a regulated iron-dependent cell death characterized by the accumulation of lipid peroxidation. A myriad of facets linking amino acid, lipid, redox, and iron metabolisms were found to drive or to suppress the execution of ferroptosis. However, how the cells decipher the diverse pro-ferroptotic stress to activate ferroptosis remains elusive. Here, we report that protein O-GlcNAcylation, the primary nutrient sensor of glucose flux, orchestrates both ferritinophagy and mitophagy for ferroptosis. Following the treatment of ferroptosis stimuli such as RSL3, a commonly used ferroptosis inducer, there exists a biphasic change of protein O-GlcNAcylation to modulate ferroptosis. Pharmacological or genetic inhibition of O-GlcNAcylation promoted ferritinophagy, resulting in the accumulation of labile iron towards mitochondria. Inhibition of O-GlcNAcylation resulted in mitochondria fragmentation and enhanced mitophagy, providing an additional source of labile iron and rendering the cell more sensitive to ferroptosis. Mechanistically, we found that de-O-GlcNAcylation of the ferritin heavy chain at S179 promoted its interaction with NCOA4, the ferritinophagy receptor, thereby accumulating labile iron for ferroptosis. Our findings reveal a previously uncharacterized link of dynamic O-GlcNAcylation with iron metabolism and decision-making for ferroptosis, thus offering potential therapeutic intervention for fighting disease.
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35
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Eshraghi M, Ahmadi M, Afshar S, Lorzadeh S, Adlimoghaddam A, Rezvani Jalal N, West R, Dastghaib S, Igder S, Torshizi SRN, Mahmoodzadeh A, Mokarram P, Madrakian T, Albensi BC, Łos MJ, Ghavami S, Pecic S. Enhancing autophagy in Alzheimer's disease through drug repositioning. Pharmacol Ther 2022; 237:108171. [PMID: 35304223 DOI: 10.1016/j.pharmthera.2022.108171] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/18/2022] [Accepted: 03/08/2022] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is one of the biggest human health threats due to increases in aging of the global population. Unfortunately, drugs for treating AD have been largely ineffective. Interestingly, downregulation of macroautophagy (autophagy) plays an essential role in AD pathogenesis. Therefore, targeting autophagy has drawn considerable attention as a therapeutic approach for the treatment of AD. However, developing new therapeutics is time-consuming and requires huge investments. One of the strategies currently under consideration for many diseases is "drug repositioning" or "drug repurposing". In this comprehensive review, we have provided an overview of the impact of autophagy on AD pathophysiology, reviewed the therapeutics that upregulate autophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD. In addition, we discussed the potential of applying nano-drug delivery to neurodegenerative diseases, such as AD, to overcome the challenge of crossing the blood brain barrier and specifically target molecules/pathways of interest with minimal side effects.
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Affiliation(s)
- Mehdi Eshraghi
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada
| | - Mazaher Ahmadi
- Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Afshar
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada
| | - Aida Adlimoghaddam
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; St. Boniface Hospital Albrechtsen Research Centre, Division of Neurodegenerative Disorders, Winnipeg, MB R2H2A6, Canada
| | | | - Ryan West
- Department of Chemistry and Biochemistry, California State University, Fullerton, United States of America
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz Iran
| | - Somayeh Igder
- Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Amir Mahmoodzadeh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tayyebeh Madrakian
- Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Benedict C Albensi
- St. Boniface Hospital Albrechtsen Research Centre, Division of Neurodegenerative Disorders, Winnipeg, MB R2H2A6, Canada; Nova Southeastern Univ. College of Pharmacy, Davie, FL, United States of America; University of Manitoba, College of Medicine, Winnipeg, MB R3E 0V9, Canada
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institutes of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB R3E 0V9, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Stevan Pecic
- Department of Chemistry and Biochemistry, California State University, Fullerton, United States of America.
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36
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Kang WS, Lee SM, Hwang D, Park HJ, Kim JW. Association between Unc-51-like autophagy activating kinase 2 gene polymorphisms and schizophrenia in the Korean population. Medicine (Baltimore) 2022; 101:e28745. [PMID: 35119028 PMCID: PMC8812592 DOI: 10.1097/md.0000000000028745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 01/08/2022] [Indexed: 01/04/2023] Open
Abstract
Accumulating evidence indicates that the autophagy process is involved in the pathogenesis of schizophrenia. Autophagy plays a fundamental role in neuronal survival and function, and autophagy-related genes have been suggested to be associated with the pathogenesis of schizophrenia. The Unc-51-like autophagy activating kinase 2 (ULK2) gene has been implicated in autophagy regulation; therefore, we hypothesized that ULK2 polymorphisms may be associated with schizophrenia susceptibility.This study explored the association between polymorphisms of ULK2 and schizophrenia.Two single nucleotide polymorphisms (SNPs) (rs55730189 and rs150122) of ULK2 were genotyped in 279 patients with schizophrenia and 403 healthy individuals using Fluidigm SNPtype assays. We analyzed the genotype distribution of 2 SNPs and haplotypes between patients with schizophrenia and control subjects.The T allele frequency of rs55730189 showed a significant association between patients with schizophrenia and control subjects (P = .003). Genotype frequencies of rs55710189 were found to be significantly different between patients with schizophrenia and control subjects (odds ratio = 6.89, 95% confidence interval = 1.91-24.90, P < .001 in the dominant model [C/T + T/T vs C/C], OR = 6.50, 95% confidence interval = 1.83-23.01, P < .001 in the log-additive model (C/T vs T/T vs C/C)]. In haplotype analysis, the TT haplotype for these 2 SNPs was significantly associated with schizophrenia (P < .001, χ2 = 12.231).Our findings suggest that specific ULK2 polymorphisms may be associated with susceptibility to schizophrenia in the Korean population.
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Affiliation(s)
- Won Sub Kang
- Department of Neuropsychiatry, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Sang Min Lee
- Department of Neuropsychiatry, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Dongkee Hwang
- Department of Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Hae Jeong Park
- Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jong Woo Kim
- Department of Neuropsychiatry, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
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37
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The complex interplay between autophagy and cell death pathways. Biochem J 2022; 479:75-90. [PMID: 35029627 DOI: 10.1042/bcj20210450] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 12/26/2022]
Abstract
Autophagy is a universal cellular homeostatic process, required for the clearance of dysfunctional macromolecules or organelles. This self-digestion mechanism modulates cell survival, either directly by targeting cell death players, or indirectly by maintaining cellular balance and bioenergetics. Nevertheless, under acute or accumulated stress, autophagy can also contribute to promote different modes of cell death, either through highly regulated signalling events, or in a more uncontrolled inflammatory manner. Conversely, apoptotic or necroptotic factors have also been implicated in the regulation of autophagy, while specific factors regulate both processes. Here, we survey both earlier and recent findings, highlighting the intricate interaction of autophagic and cell death pathways. We, Furthermore, discuss paradigms, where this cross-talk is disrupted, in the context of disease.
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38
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Liao HY, Wang ZQ, Ran R, Zhou KS, Ma CW, Zhang HH. Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury. Front Cell Dev Biol 2022; 9:761273. [PMID: 34988074 PMCID: PMC8721099 DOI: 10.3389/fcell.2021.761273] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal degradation pathway that maintains metabolism and homeostasis by eliminating protein aggregates and damaged organelles. Many studies have reported that autophagy plays an important role in spinal cord injury (SCI). However, the spatiotemporal patterns of autophagy activation after traumatic SCI are contradictory. Most studies show that the activation of autophagy and inhibition of apoptosis have neuroprotective effects on traumatic SCI. However, reports demonstrate that autophagy is strongly associated with distal neuronal death and the impaired functional recovery following traumatic SCI. This article introduces SCI pathophysiology, the physiology and mechanism of autophagy, and our current review on its role in traumatic SCI. We also discuss the interaction between autophagy and apoptosis and the therapeutic effect of activating or inhibiting autophagy in promoting functional recovery. Thus, we aim to provide a theoretical basis for the biological therapy of SCI.
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Affiliation(s)
- Hai-Yang Liao
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Zhi-Qiang Wang
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Rui Ran
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Kai-Sheng Zhou
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Chun-Wei Ma
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Hai-Hong Zhang
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
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39
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Ghafarkhani M, Avci CB, Rahbarghazi R, Karimi A, Sadeghizadeh M, Zarebkohan A, Bani F. Mild hyperthermia induced by gold nanorods acts as a dual-edge blade in the fate of SH-SY5Y cells via autophagy. Sci Rep 2021; 11:23984. [PMID: 34907215 PMCID: PMC8671444 DOI: 10.1038/s41598-021-02697-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023] Open
Abstract
Unraveling unwanted side effects of nanotechnology-based therapies like photothermal therapy (PTT) is vital in translational nanomedicine. Herein, we monitored the relationship between autophagic response at the transcriptional level by using a PCR array and tumor formation ability by colony formation assay in the human neuroblastoma cell line, SH-SY5Y, 48 h after being exposed to two different mild hyperthermia (43 and 48 °C) induced by PTT. In this regard, the promotion of apoptosis and autophagy were evaluated using immunofluorescence imaging and flow cytometry analyses. Protein levels of Ki-67, P62, and LC3 were measured using ELISA. Our results showed that of 86 genes associated with autophagy, the expression of 54 genes was changed in response to PTT. Also, we showed that chaperone-mediated autophagy (CMA) and macroautophagy are stimulated in PTT. Importantly, the results of this study also showed significant changes in genes related to the crosstalk between autophagy, dormancy, and metastatic activity of treated cells. Our findings illustrated that PTT enhances the aggressiveness of cancer cells at 43 °C, in contrast to 48 °C by the regulation of autophagy-dependent manner.
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Affiliation(s)
- Maryam Ghafarkhani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran
| | - Cigir Biray Avci
- Department of Medical Biology, Medical Faculty, Ege University, Bornova, 35100, Izmir, Turkey
| | - Reza Rahbarghazi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Karimi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Sadeghizadeh
- Department of Nanobiotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Zarebkohan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Farhad Bani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Raha S, Ghosh A, Dutta D, Patel DR, Pahan K. Activation of PPARα enhances astroglial uptake and degradation of β-amyloid. Sci Signal 2021; 14:eabg4747. [PMID: 34699252 DOI: 10.1126/scisignal.abg4747] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Sumita Raha
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Arunava Ghosh
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Debashis Dutta
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Dhruv R Patel
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Kalipada Pahan
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.,Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA
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Lashley T, Tossounian MA, Costello Heaven N, Wallworth S, Peak-Chew S, Bradshaw A, Cooper JM, de Silva R, Srai SK, Malanchuk O, Filonenko V, Koopman MB, Rüdiger SGD, Skehel M, Gout I. Extensive Anti-CoA Immunostaining in Alzheimer's Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A. Front Cell Neurosci 2021; 15:739425. [PMID: 34720880 PMCID: PMC8554225 DOI: 10.3389/fncel.2021.739425] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 09/17/2021] [Indexed: 11/13/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1β cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions.
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Affiliation(s)
- Tammaryn Lashley
- Queen Square Brain Bank, UCL Queen Square Institute of Neurology, London, United Kingdom
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Maria-Armineh Tossounian
- Department of Structural and Molecular Biology, University College London, London, United Kingdom
| | - Neve Costello Heaven
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
- Department of Structural and Molecular Biology, University College London, London, United Kingdom
| | - Samantha Wallworth
- Department of Structural and Molecular Biology, University College London, London, United Kingdom
| | - Sew Peak-Chew
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Aaron Bradshaw
- Department of Molecular Neuroscience, Faculty of Brain Sciences, Royal Free Campus, London, United Kingdom
| | - J. Mark Cooper
- Department of Molecular Neuroscience, Faculty of Brain Sciences, Royal Free Campus, London, United Kingdom
| | - Rohan de Silva
- Reta Lila Weston Institute of Neurological Studies, University College London, London, United Kingdom
| | - Surjit Kaila Srai
- Department of Structural and Molecular Biology, University College London, London, United Kingdom
| | - Oksana Malanchuk
- Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, Ukraine
| | - Valeriy Filonenko
- Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, Ukraine
| | - Margreet B. Koopman
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
- Science for Life, Utrecht University, Utrecht, Netherlands
| | - Stefan G. D. Rüdiger
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
- Science for Life, Utrecht University, Utrecht, Netherlands
| | - Mark Skehel
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Ivan Gout
- Department of Structural and Molecular Biology, University College London, London, United Kingdom
- Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, Ukraine
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Iyaswamy A, Krishnamoorthi SK, Zhang H, Sreenivasmurthy SG, Zhu Z, Liu J, Su CF, Guan XJ, Wang ZY, Cheung KH, Song JX, Durairajan SSK, Li M. Qingyangshen mitigates amyloid-β and Tau aggregate defects involving PPARα-TFEB activation in transgenic mice of Alzheimer's disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 91:153648. [PMID: 34332287 DOI: 10.1016/j.phymed.2021.153648] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 06/01/2021] [Accepted: 06/30/2021] [Indexed: 05/26/2023]
Abstract
BACKGROUND Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs) is the key pathological hallmark of AD. Accumulating evidence suggest that impairment of autophagy-lysosomal pathway (ALP) plays key roles in AD pathology. PURPOSE The present study aims to assess the neuroprotective effects of Qingyangshen (QYS), a Chinese herbal medicine, in AD cellular and animal models and to determine its underlying mechanisms involving ALP regulation. METHODS QYS extract was prepared and its chemical components were characterized by LC/MS. Then the pharmacokinetics and acute toxicity of QYS extract were evaluated. The neuroprotective effects of QYS extract were determined in 3XTg AD mice, by using a series of behavioral tests and biochemical assays, and the mechanisms were examined in vitro. RESULTS Oral administration of QYS extract improved learning and spatial memory, reduced carboxy-terminal fragments (CTFs), amyloid precursor protein (APP), Aβ and Tau aggregates, and inhibited microgliosis and astrocytosis in the brains of 3XTg mice. Mechanistically, QYS extract increased the expression of PPARα and TFEB, and promoted ALP both in vivo and in vitro. CONCLUSION QYS attenuates AD pathology, and improves cognitive function in 3XTg mice, which may be mediated by activation of PPARα-TFEB pathway and the subsequent ALP enhancement. Therefore, QYS may be a promising herbal material for further anti-AD drug discovery.
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Affiliation(s)
- Ashok Iyaswamy
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Senthil Kumar Krishnamoorthi
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Huan Zhang
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Sravan G Sreenivasmurthy
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Zhou Zhu
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Jia Liu
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Cheng-Fu Su
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Xin-Jie Guan
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Zi-Ying Wang
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Interdisciplinary Institute for Personalized Medicine in Brain Disorders, Jinan University, Guangzhou, China
| | - King-Ho Cheung
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Ju-Xian Song
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Siva Sundara Kumar Durairajan
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Division of Mycobiology and Neurodegenerative disease research, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur, India.
| | - Min Li
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
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Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β. J Biol Chem 2021; 297:101159. [PMID: 34480901 PMCID: PMC8477193 DOI: 10.1016/j.jbc.2021.101159] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and AppNL-F/NL-F knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer–induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading.
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Rana T, Behl T, Sehgal A, Mehta V, Singh S, Bhatia S, Al-Harrasi A, Bungau S. Exploring the Role of Autophagy Dysfunction in Neurodegenerative Disorders. Mol Neurobiol 2021; 58:4886-4905. [PMID: 34212304 DOI: 10.1007/s12035-021-02472-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022]
Abstract
Autophagy is a catabolic pathway by which misfolded proteins or damaged organelles are engulfed by autophagosomes and then transported to lysosomes for degradation. Recently, a great improvement has been done to explain the molecular mechanisms and roles of autophagy in several important cellular metabolic processes. Besides being a vital clearance pathway or a cell survival pathway in response to different stresses, autophagy dysfunction, either upregulated or down-regulated, has been suggested to be linked with numerous neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Impairment at different stages of autophagy results in the formation of large protein aggregates and damaged organelles, which leads to the onset and progression of different neurodegenerative disorders. This article elucidates the recent progress about the role of autophagy in neurodegenerative disorders and explains how autophagy dysfunction is linked with the pathogenesis of such disorders as well as the novel potential autophagy-associated therapies for treating them.
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Affiliation(s)
- Tarapati Rana
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
- Government Pharmacy College, Seraj, Mandi, Himachal Pradesh, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Vineet Mehta
- Government College of Pharmacy, Rohru, Distt. Shimla, Himachal Pradesh, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Haryana, India
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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Luft C, Haute GV, Wearick-Silva LE, Antunes KH, da Costa MS, de Oliveira JR, Donadio MVF. Prenatal stress and KCl-induced depolarization modulate cell death, hypothalamic-pituitary-adrenal axis genes, oxidative and inflammatory response in primary cortical neurons. Neurochem Int 2021; 147:105053. [PMID: 33961947 DOI: 10.1016/j.neuint.2021.105053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/01/2021] [Accepted: 04/24/2021] [Indexed: 12/27/2022]
Abstract
Maternal stress has been described as an important component in the offspring's cerebral development, altering the susceptibility to diseases in later life. Moreover, the postnatal period is essential for the development and integration of several peripheral and central systems related to the control of homeostasis. Thus, this study aimed to evaluate the effects of prenatal stress on the activation of cortical neurons, by performing experiments both under basal conditions and after KCl-induced depolarization. Female mice were divided in two groups: control and prenatal restraint stress. Cortical neurons from the offspring were obtained at gestational day 18. The effects of prenatal stress and KCl stimulations on cellular mortality, autophagy, gene expression, oxidative stress, and inflammation were evaluated. We found that neurons from PNS mice have decreased necrosis and autophagy after depolarization. Moreover, prenatal stress modulated the HPA axis, as observed by the increased GR and decreased 5HTr1 mRNA expression. The BDNF is an important factor for neuronal function and results demonstrated that KCl-induced depolarization increased the gene expression of BDNF I, BDNF IV, and TRκB. Furthermore, prenatal stress and KCl treatment induced significant alterations in oxidative and inflammatory markers. In conclusion, prenatal stress and stimulation with KCl may influence several markers related to neurodevelopment in cortical neurons from neonate mice, supporting the well-known long-term effects of maternal stress.
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Affiliation(s)
- Carolina Luft
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Gabriela Viegas Haute
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Luís Eduardo Wearick-Silva
- Exercise, Behavior and Cognition Research Group, Psychology Department, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Krist Helen Antunes
- Laboratory of Clinical and Experimental Immunology, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Mariana Severo da Costa
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Jarbas Rodrigues de Oliveira
- Laboratory of Cellular Biophysics and Inflammation, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Márcio Vinícius Fagundes Donadio
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
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Bonadio RS, Nunes LB, Moretti PNS, Mazzeu JF, Cagnin S, Pic-Taylor A, de Oliveira SF. Insights into how environment shapes post-mortem RNA transcription in mouse brain. Sci Rep 2021; 11:13008. [PMID: 34155272 PMCID: PMC8217559 DOI: 10.1038/s41598-021-92268-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/27/2021] [Indexed: 02/05/2023] Open
Abstract
Most biological features that occur on the body after death were already deciphered by traditional medicine. However, the molecular mechanisms triggered in the cellular microenvironment are not fully comprehended yet. Previous studies reported gene expression alterations in the post-mortem condition, but little is known about how the environment could influence RNA degradation and transcriptional regulation. In this work, we analysed the transcriptome of mouse brain after death under three concealment simulations (air exposed, buried, and submerged). Our analyses identified 2,103 genes differentially expressed in all tested groups 48 h after death. Moreover, we identified 111 commonly upregulated and 497 commonly downregulated genes in mice from the concealment simulations. The gene functions shared by the individuals from the tested environments were associated with RNA homeostasis, inflammation, developmental processes, cell communication, cell proliferation, and lipid metabolism. Regarding the altered biological processes, we identified that the macroautophagy process was enriched in the upregulated genes and lipid metabolism was enriched in the downregulated genes. On the other hand, we also described a list of biomarkers associated with the submerged and buried groups, indicating that these environments can influence the post-mortem RNA abundance in its particular way.
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Affiliation(s)
- Raphael Severino Bonadio
- grid.7632.00000 0001 2238 5157Department of Genetics and Morphology, University of Brasilia, Brasilia, Brazil ,grid.5608.b0000 0004 1757 3470Department of Biology and CRIBI Biotechnology Centre, University of Padova, Padova, Italy
| | - Larissa Barbosa Nunes
- grid.7632.00000 0001 2238 5157Department of Genetics and Morphology, University of Brasilia, Brasilia, Brazil
| | | | - Juliana Forte Mazzeu
- grid.7632.00000 0001 2238 5157Faculty of Medicine, University of Brasilia, Brasilia, Brazil
| | - Stefano Cagnin
- grid.5608.b0000 0004 1757 3470Department of Biology and CRIBI Biotechnology Centre, University of Padova, Padova, Italy
| | - Aline Pic-Taylor
- grid.7632.00000 0001 2238 5157Department of Genetics and Morphology, University of Brasilia, Brasilia, Brazil
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Jo YR, Kim HR, Jang SY, Go H, Song MY, Park DK, Oh Y, Jo J, Shin YK, Lee SJ, Cheon SM, Lee HK, Lee KE, Kim YH, Park HT. Potential neuron-autonomous Purkinje cell degeneration by 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter/Cre-mediated autophagy impairments. FASEB J 2021; 35:e21225. [PMID: 33337568 DOI: 10.1096/fj.202001366rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 11/04/2020] [Accepted: 11/11/2020] [Indexed: 11/11/2022]
Abstract
Studies of neuroglial interaction largely depend on cell-specific gene knockout (KO) experiments using Cre recombinase. However, genes known as glial-specific genes have recently been reported to be expressed in neuroglial stem cells, leading to the possibility that a glia-specific Cre driver results in unwanted gene deletion in neurons, which may affect sound interpretation. 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) is generally considered to be an oligodendrocyte (OL) marker. Accordingly, Cnp promoter-controlled Cre recombinase has been used to create OL-specific gene targeting mice. However, in this study, using Rosa26-tdTomato-reporter/Cnp-Cre mice, we found that many forebrain neurons and cerebellar Purkinje neurons belong to the lineages of Cnp-expressing neuroglial stem cells. To answer whether gene targeting by Cnp-Cre can induce neuron-autonomous defects, we conditionally deleted an essential autophagy gene, Atg7, in Cnp-Cre mice. The Cnp-Cre-mediated Atg7 KO mice showed extensive p62 inclusion in neurons, including cerebellar Purkinje neurons with extensive neurodegeneration. Furthermore, neuronal areas showing p62 inclusion in Cnp-Cre-mediated Atg7 KO mice overlapped with the neuronal lineage of Cnp-expressing neuroglial stem cells. Moreover, Cnp-Cre-mediated Atg7-KO mice did not develop critical defects in myelination. Our results demonstrate that a large population of central neurons are derived from Cnp-expressing neuroglial stem cells; thus, conditional gene targeting using the Cnp promoter, which is known to be OL-specific, can induce neuron-autonomous phenotypes.
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Affiliation(s)
- Young Rae Jo
- Peripheral Neuropathy Research Center (PNRC), Department of Molecular Neuroscience, College of Medicine, Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Dong-A University, Busan, Republic of Korea
| | - Hye Ran Kim
- Peripheral Neuropathy Research Center (PNRC), Department of Molecular Neuroscience, College of Medicine, Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Dong-A University, Busan, Republic of Korea
| | - So Young Jang
- Peripheral Neuropathy Research Center (PNRC), Department of Molecular Neuroscience, College of Medicine, Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Dong-A University, Busan, Republic of Korea
| | - Hana Go
- Peripheral Neuropathy Research Center (PNRC), Department of Molecular Neuroscience, College of Medicine, Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Dong-A University, Busan, Republic of Korea
| | - Min-Young Song
- Biomedical Omics Group, Korea Basic Science Institute, Cheongju-si, Republic of Korea
| | - Da Kyeong Park
- Biomedical Omics Group, Korea Basic Science Institute, Cheongju-si, Republic of Korea
| | - Yuna Oh
- Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Juyeon Jo
- Department of Pediatrics at Baylor College of Medicine, Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA
| | - Yoon Kyung Shin
- Peripheral Neuropathy Research Center (PNRC), Department of Molecular Neuroscience, College of Medicine, Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Dong-A University, Busan, Republic of Korea
| | - Sung Joong Lee
- Department of Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Sang-Myung Cheon
- Department of Neurology, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Hyun Kyoung Lee
- Department of Pediatrics at Baylor College of Medicine, Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA
| | - Kyung Eun Lee
- Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Young Hye Kim
- Biomedical Omics Group, Korea Basic Science Institute, Cheongju-si, Republic of Korea
| | - Hwan Tae Park
- Peripheral Neuropathy Research Center (PNRC), Department of Molecular Neuroscience, College of Medicine, Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Dong-A University, Busan, Republic of Korea
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Fu SC, Lin JW, Liu JM, Liu SH, Fang KM, Su CC, Hsu RJ, Wu CC, Huang CF, Lee KI, Chen YW. Arsenic induces autophagy-dependent apoptosis via Akt inactivation and AMPK activation signaling pathways leading to neuronal cell death. Neurotoxicology 2021; 85:133-144. [PMID: 34038756 DOI: 10.1016/j.neuro.2021.05.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 05/18/2021] [Accepted: 05/18/2021] [Indexed: 12/19/2022]
Abstract
Inorganic arsenic (As3+), a well-known worldwide industrial and environmental pollutant, has been linked to neurodegenerative disorders (NDs). Autophagy plays an important role in controlling neuronal cell survival/death. However, limited information is available regarding the toxicological mechanism at the interplay between autophagy and As3+-induced neurotoxicity. The present study found that As3+ exposure induced a concomitant activation of apoptosis and autophagy in Neuro-2a cells, which was accompanied with the increase of phosphatidylserine exposure on outer membrane leaflets and apoptotic cell population, and the activation of caspase-3, -7, and PARP as well as the elevation of protein expressions of LC3-II, Atg-5, and Beclin-1, and the accumulation of autophagosome. Pretreatment of cells with autophagy inhibitor 3-MA, but not that of Z-VAD-FMK (a pan-caspase inhibitor), effectively prevented the As3+-induced autophagic and apoptotic responses, indicating that As3+-triggered autophagy was contributing to neuronal cell apoptosis. Furthermore, As3+ exposure evoked the dephosphorylation of Akt. Pretreatment with SC79, an Akt activator, could significantly attenuated As3+-induced Akt inactivation as well as autophagic and apoptotic events. Expectedly, inhibition of Akt signaling with LY294002 obviously enhanced As3+-triggered autophagy and apoptosis. Exposure to As3+ also dramatically increased the phosphorylation level of AMPKα. Pretreatment of AMPK inhibitor (Compound C) could markedly abrogate the As3+-induced phosphorylated AMPKα expression, and autophagy and apoptosis activation. Taken together, these results indicated that As3+ exerted its cytotoxicity in neuronal cells via the Akt inactivation/AMPK activation downstream-regulated autophagy-dependent apoptosis pathways, which ultimately lead to cell death. Our findings suggest that the regulation of Akt/AMPK signals may be a promising intervention to against As3+-induced neurotoxicity and NDs.
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Affiliation(s)
- Shih-Chang Fu
- Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, 330, Taiwan
| | - Jhe-Wei Lin
- Department of Physiology and Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, 404, Taiwan
| | - Jui-Ming Liu
- Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, 330, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
| | - Kai-Min Fang
- Department of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Chin-Chuan Su
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County, 500, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Ren-Jun Hsu
- Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, Taiwan; Biobank Management Center of Tri-Service General Hospital and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, 114, Taiwan
| | - Chin-Ching Wu
- Department of Public Health, China Medical University, Taichung, 404, Taiwan
| | - Chun-Fa Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan; Department of Nursing, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan
| | - Kuan-I Lee
- Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, 427, Taiwan.
| | - Ya-Wen Chen
- Department of Physiology and Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, 404, Taiwan.
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Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, Nixon RA, Jones DT. Alzheimer disease. Nat Rev Dis Primers 2021; 7:33. [PMID: 33986301 PMCID: PMC8574196 DOI: 10.1038/s41572-021-00269-y] [Citation(s) in RCA: 1185] [Impact Index Per Article: 296.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2021] [Indexed: 12/21/2022]
Abstract
Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic neurodegenerative disease that causes an amnestic cognitive impairment in its prototypical presentation and non-amnestic cognitive impairment in its less common variants. AD is a common cause of cognitive impairment acquired in midlife and late-life but its clinical impact is modified by other neurodegenerative and cerebrovascular conditions. This Primer conceives of AD biology as the brain disorder that results from a complex interplay of loss of synaptic homeostasis and dysfunction in the highly interrelated endosomal/lysosomal clearance pathways in which the precursors, aggregated species and post-translationally modified products of Aβ and tau play important roles. Therapeutic endeavours are still struggling to find targets within this framework that substantially change the clinical course in persons with AD.
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Affiliation(s)
| | - Helene Amieva
- Inserm U1219 Bordeaux Population Health Center, University of Bordeaux, Bordeaux, France
| | | | - Gäel Chételat
- Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, Caen, France
| | - David M Holtzman
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
| | - Bradley T Hyman
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Ralph A Nixon
- Departments of Psychiatry and Cell Biology, New York University Langone Medical Center, New York University, New York, NY, USA
- NYU Neuroscience Institute, New York University Langone Medical Center, New York University, New York, NY, USA
| | - David T Jones
- Department of Neurology, Mayo Clinic, Rochester, MN, USA
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Role of BDNF-mTORC1 Signaling Pathway in Female Depression. Neural Plast 2021; 2021:6619515. [PMID: 33628219 PMCID: PMC7886502 DOI: 10.1155/2021/6619515] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/22/2021] [Indexed: 12/18/2022] Open
Abstract
Depression is a common psychological and mental disorder, characterized by low mood, slow thinking and low will, and even suicidal tendencies in severe cases. It imposes a huge mental and economic burden on patients and their families, and its prevention and treatment have become an urgent public health problem. It is worth noting that there is a significant gender difference in the incidence of depression. Studies have shown that females are far more likely to suffer from depression than males, confirming a close relationship between estrogen and the onset of depression. Moreover, recent studies suggest that the brain-derived neurotrophic factor- (BDNF-) mammalian target of rapamycin complex-1 (mTORC1) signaling pathway is a crucial target pathway for improving depression and mediates the rapid antidepressant-like effects of various antidepressants. However, it is not clear whether the BDNF-mTORC1 signaling pathway mediates the regulation of female depression and how to regulate female depression. Hence, we focused on the modulation of estrogen-BDNF-mTORC1 signaling in depression and its possible mechanisms in recent years.
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