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1
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Seluzicki CM, Razavi-Mohseni M, Türker F, Patel P, Hua B, Beer MA, Goff L, Margolis SS. Regulation of translation elongation and integrated stress response in heat-shocked neurons. Cell Rep 2025; 44:115639. [PMID: 40286269 DOI: 10.1016/j.celrep.2025.115639] [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: 08/21/2023] [Revised: 03/03/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
Neurons deviate from a canonical heat shock response (HSR). Here, we revealed that neuronal adaptation to heat shock accompanies a brake on mRNA translation, slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2 (p-eEF2), and suppressed the integrated stress response (ISR). Returning neurons to control temperature within 1 h of starting heat shock was necessary for survival and allowed for restored translation following dephosphorylation of eEF2. Subsequent to recovery, neurons briefly activated the ISR and were sensitive to the ISR inhibitor ISRIB, which enhanced protein synthesis and survival. Ribosome profiling and RNA sequencing (RNA-seq) identified newly synthesized and existing transcripts associated with ribosomes during heat shock. Preservation of these transcripts for translation during recovery was in part mediated by p-eEF2 and slowed ribosomes. Our work supports a neuronal heat shock model of a partially suspended state of translation poised for rapid reversal if recovery becomes an option and provides insight into regulation between the HSR and the ISR.
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Affiliation(s)
- Caitlin M Seluzicki
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Milad Razavi-Mohseni
- Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Fulya Türker
- Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey
| | - Priyal Patel
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Boyang Hua
- Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Michael A Beer
- Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Loyal Goff
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Seth S Margolis
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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2
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Smadja DM, Abreu MM. Hyperthermia and targeting heat shock proteins: innovative approaches for neurodegenerative disorders and Long COVID. Front Neurosci 2025; 19:1475376. [PMID: 39967803 PMCID: PMC11832498 DOI: 10.3389/fnins.2025.1475376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 01/03/2025] [Indexed: 02/20/2025] Open
Abstract
Neurodegenerative diseases (NDs) and Long COVID represent critical and growing global health challenges, characterized by complex pathophysiological mechanisms including neuronal deterioration, protein misfolding, and persistent neuroinflammation. The emergence of innovative therapeutic approaches, such as whole-body hyperthermia (WBH), offers promising potential to modulate underlying pathophysiological mechanisms in NDs and related conditions like Long COVID. WBH, particularly in fever-range, enhances mitochondrial function, induces heat shock proteins (HSPs), and modulates neuroinflammation-benefits that pharmacological treatments often struggle to replicate. HSPs such as HSP70 and HSP90 play pivotal roles in protein folding, aggregation prevention, and cellular protection, directly targeting pathological processes seen in NDs like Alzheimer's, Parkinson's, and Huntington's disease. Preliminary findings also suggest WBH's potential to alleviate neurological symptoms in Long COVID, where persistent neuroinflammation and serotonin dysregulation are prominent. Despite the absence of robust clinical trials, the therapeutic implications of WBH extend to immune modulation and the restoration of disrupted physiological pathways. However, the dual nature of hyperthermia's effects-balancing pro-inflammatory and anti-inflammatory responses-emphasizes the need for dose-controlled applications and stringent patient monitoring to minimize risks in vulnerable populations. While WBH shows potential interest, significant challenges remain. These include individual variability in response, limited accessibility to advanced hyperthermia technologies, and the need for standardized clinical protocols. Future research must focus on targeted clinical trials, biomarker identification, and personalized treatment strategies to optimize WBH's efficacy in NDs and Long COVID. The integration of WBH into therapeutic paradigms could mark a transformative step in addressing these complex conditions.
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Affiliation(s)
- David M. Smadja
- Paris Cité University, INSERM, Paris Cardiovascular Research Centre, Team Endotheliopathy and Hemostasis Disorders, Paris, France
- Hematology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris-Centre Université Paris Cité (APHP-CUP), Paris, France
| | - M. Marc Abreu
- BTT Medical Institute, Aventura, FL, United States
- BTT Engineering Department, Aventura, FL, United States
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3
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Almutary AG, Begum MY, Kyada AK, Gupta S, Jyothi SR, Chaudhary K, Sharma S, Sinha A, Abomughaid MM, Imran M, Lakhanpal S, Babalghith AO, Abu-Seer EA, Avinash D, Alzahrani HA, Alhindi AA, Iqbal D, Kumar S, Jha NK, Alghamdi S. Inflammatory signaling pathways in Alzheimer's disease: Mechanistic insights and possible therapeutic interventions. Ageing Res Rev 2025; 104:102548. [PMID: 39419399 DOI: 10.1016/j.arr.2024.102548] [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: 01/26/2024] [Revised: 10/09/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024]
Abstract
The complex pathophysiology of Alzheimer's disease (AD) poses challenges for the development of therapies. Recently, neuroinflammation has been identified as a key pathogenic mechanism underlying AD, while inflammation has emerged as a possible target for the management and prevention of AD. Several prior studies have demonstrated that medications modulating neuroinflammation might lessen AD symptoms, mostly by controlling neuroinflammatory signaling pathways such as the NF-κB, MAPK, NLRP3, etc, and their respective signaling cascade. Moreover, targeting these inflammatory modalities with inhibitors, natural products, and metabolites has been the subject of intensive research because of their anti-inflammatory characteristics, with many studies demonstrating noteworthy pharmacological capabilities and potential clinical applications. Therefore, targeting inflammation is considered a promising strategy for treating AD. This review comprehensively elucidates the neuroinflammatory mechanisms underlying AD progression and the beneficial effects of inhibitors, natural products, and metabolites in AD treatment.
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Affiliation(s)
- Abdulmajeed G Almutary
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, P.O. Box 59911, Abu Dhabi, United Arab Emirates
| | - M Yasmin Begum
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Ashish Kumar Kyada
- Marwadi University Research Center, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Marwadi University, Rajkot, Gujarat 360003, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India
| | - S Renuka Jyothi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Swati Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, Punjab 140307, India
| | - Aashna Sinha
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand
| | - Mosleh Mohammad Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia; Center for Health Research, Northern Border University, Arar, Saudi Arabia
| | - Sorabh Lakhanpal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Ahmad O Babalghith
- Medical Genetics Department, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Eman Adnan Abu-Seer
- Department of Epidemiology and Medical Statistic, Faculty of Public Health and Health Informatics, Umm Al-Qura University, Makkah, Saudi Arabia
| | - D Avinash
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Hassan A Alzahrani
- Department of Respiratory Care, Medical Cities at the Minister of Interior, MCMOl, Riyadh, Saudi Arabia
| | | | - Danish Iqbal
- Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia
| | - Sandeep Kumar
- School of Pharmacy, Sharda University, Greater Noida, India; DST-FIST Laboratory, Sharda University, Greater Noida, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Biosciences and Technology (SBT), Galgotias University, Greater Noida, India; Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, India.
| | - Saad Alghamdi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
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Valle-Medina A, Calzada-Mendoza CC, Ocharan-Hernández ME, Jiménez-Zamarripa CA, Juárez-Cedillo T. Heat shock protein 70 in Alzheimer's disease and other dementias: A possible alternative therapeutic. J Alzheimers Dis Rep 2025; 9:25424823241307021. [PMID: 40034501 PMCID: PMC11864251 DOI: 10.1177/25424823241307021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 11/03/2024] [Indexed: 03/05/2025] Open
Abstract
Alzheimer's disease (AD) is considered a global health issue with a high social burden due to the level of disability it causes in those who suffer from it. In the absence of a therapeutic alternative for this disease, we will follow one of the biochemical pathways involved in the development of AD, which is related to molecular chaperones. The molecules are responsible for eliminating toxins and misfolded proteins at the cerebral level. These chaperones are a set of proteins from the heat shock proteins (HSPs) family, which, among their functions, help maintain homeostasis and protect cells against stress. Various authors have described the activity of HSPs in different neurodegenerative diseases, highlighting the activity of heat shock protein 70 (HSP70) in the presence of aberrant proteins characteristic of neurodegeneration, such as amyloid-β (Aβ) and tau. The role of HSP70 in AD and other dementias lies in its mechanism, which, along with other proteins from the HSP family, has the capacity to eliminate Aβ aggregates by promoting catalytic pathways. In this review, we explore the biological role of the HSP70 protein in AD and other dementias and its potential therapeutic use.
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Affiliation(s)
- Antonio Valle-Medina
- Laboratorio 107 señalización celular, Edificio de Graduados, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, México
| | - Claudia Camelia Calzada-Mendoza
- Laboratorio 107 señalización celular, Edificio de Graduados, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, México
| | - María Esther Ocharan-Hernández
- Laboratorio 107 señalización celular, Edificio de Graduados, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, México
| | - Carlos Alberto Jiménez-Zamarripa
- Laboratorio 107 señalización celular, Edificio de Graduados, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, México
| | - Teresa Juárez-Cedillo
- Unidad de Investigación Médica en Epidemiología Clínica, Unidad Médica de Alta Especialidad “Hospital de Pediatría Dr Silvestre Frenk Freund”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, México
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5
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Wu CC, Meyer DN, Haimbaugh A, Baker TR. Implications of Lead (Pb)-Induced Transcriptomic and Phenotypic Alterations in the Aged Zebrafish ( Danio rerio). TOXICS 2024; 12:745. [PMID: 39453165 PMCID: PMC11511149 DOI: 10.3390/toxics12100745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/26/2024]
Abstract
Lead (Pb) is a well-known neurotoxin with established adverse effects on the neurological functions of children and younger adults, including motor, learning, and memory abilities. However, its potential impact on older adults has received less attention. Using the zebrafish model, our study aims to characterize the dose-response relationship between environmentally relevant Pb exposure levels and their effects on changes in behavior and transcriptomics during the geriatric periods. We exposed two-year-old zebrafish to waterborne lead acetate (1, 10, 100, 1000, or 10,000 µg/L) or a vehicle (DMSO) for 5 days. While lower concentrations (1-100 µg/L) reflect environmentally relevant Pb levels, higher concentrations (1000-10,000 µg/L) were included to assess acute toxicity under extreme exposure scenarios. We conducted adult behavior assessment to evaluate the locomotor activity following exposure. The same individual fish were subsequently sacrificed for brain dissection after a day of recovery in the aquatic system. RNA extraction and sequencing were then performed to evaluate the Pb-induced transcriptomic changes. Higher (1000-10,000 ug/L) Pb levels induced hyperactive locomotor patterns in aged zebrafish, while lower (10-100 ug/L) Pb levels resulted in the lowest locomotor activity compared to the control group. Exposure to 100 µg/L led to the highest number of differentially expressed genes (DEGs), while 10,000 µg/L induced larger fold changes in both directions. The neurological pathways impacted by Pb exposure include functions related to neurotransmission, such as cytoskeletal regulation and synaptogenesis, and oxidative stress response, such as mitochondrial dysfunction and downregulation of heat shock protein genes. These findings emphasize a U-shape dose-response relationship with Pb concentrations in locomotor activity and transcriptomic changes in the aging brain.
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Affiliation(s)
- Chia-Chen Wu
- Institute of Environmental Engineering, National Yang Ming Chiao Tung University, 1001, Daxue Rd, East District, Hsinchu City 300093, Taiwan;
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
| | - Danielle N. Meyer
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
- Department of Pharmacology, School of Medicine, Wayne State University, 540 E. Canfield, Detroit, MI 48201, USA
| | - Alex Haimbaugh
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
- Department of Pharmacology, School of Medicine, Wayne State University, 540 E. Canfield, Detroit, MI 48201, USA
| | - Tracie R. Baker
- Department of Environmental and Global Health, University of Florida, 1225 Center Drive, Gainesville, FL 32610, USA; (D.N.M.)
- Department of Pharmacology, School of Medicine, Wayne State University, 540 E. Canfield, Detroit, MI 48201, USA
- UF Genetics Institute, University of Florida, 2033 Mowry Road, Gainesville, FL 32610, USA
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6
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Vinokurov AY, Palalov AA, Kritskaya KA, Demyanenko SV, Garbuz DG, Evgen'ev MB, Esteras N, Abramov AY. Cell-Permeable HSP70 Protects Neurons and Astrocytes Against Cell Death in the Rotenone-Induced and Familial Models of Parkinson's Disease. Mol Neurobiol 2024; 61:7785-7795. [PMID: 38429623 DOI: 10.1007/s12035-024-04077-9] [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: 09/29/2023] [Accepted: 02/07/2024] [Indexed: 03/03/2024]
Abstract
Heat shock protein 70 (HSP70) is activated under stress response. Its involvement in cell protection, including energy metabolism and quality control makes it a promising pharmacological target. A strategy to increase HSP70 levels inside the cells is the application of recombinant HSP70. However, cell permeability and functionality of these exogenously applied proteins inside the cells is still disputable. Here, using fluorescence- labeled HSP70, we have studied permeability and distribution of HSP70 inside primary neurons and astrocytes, and how exogenous HSP70 changes mitochondrial metabolism and mitophagy. We have found that exogenous recombinant HSP70 can penetrate the neurons and astrocytes and distributes in mitochondria, lysosomes and in lesser degree in the endoplasmic reticulum. HSP70 increases mitochondrial membrane potential in control neurons and astrocytes, and in fibroblasts of patients with familial Parkinson´s disease (PD) with PINK1 and LRRK2 mutations. Increased mitochondrial membrane potential was associated with higher mitochondrial ROS production and activation of mitophagy. Importantly, preincubation of the cells with HSP70 protected neurons and astrocytes against cell death in a toxic model of PD induced by rotenone, and in the PINK1 and LRRK2 PD human fibroblasts. Thus, exogenous recombinant HSP70 is cell permeable, and acts as endogenous HSP70 protecting cells in the case of toxic model and familial forms of Parkinson's Disease.
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Affiliation(s)
| | | | - Kristina A Kritskaya
- Institute of Cell Biophysics of the Russian Academy of Sciences, 142290, Pushchino, Russia
| | - Svetlana V Demyanenko
- Laboratory of Molecular Neurobiology, Academy of Biology and Biotechnology, Southern Federal University, 344090, Rostov-On-Don, Russia
| | - David G Garbuz
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia
| | - Michael B Evgen'ev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia
| | - Noemi Esteras
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
- Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Andrey Y Abramov
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
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Ferris E, Gonzalez Murcia JD, Cristina Rodriguez A, Steinwand S, Stacher Hörndli C, Traenkner D, Maldonado-Catala PJ, Gregg C. Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.26.600891. [PMID: 38979381 PMCID: PMC11230405 DOI: 10.1101/2024.06.26.600891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Elucidating the genetic basis of mammalian metabolism could help define mechanisms central to health and disease. Here, we define conserved cis-regulatory elements (CREs) and programs for mammalian metabolic control. We delineate gene expression and chromatin responses in the mouse hypothalamus for 7 steps of the Fed-to-Fasted-to-Refed (FFR) response process. Comparative genomics of hibernating versus non-hibernating lineages then illuminates cis-elements showing convergent changes in hibernators. Hibernators accumulated loss-of-function effects for specific CREs regulating hypothalamic FFR responses. Multi-omics approaches pinpoint key CREs, genes, regulatory programs, and cell types in the divergence of hibernating and homeothermic lineages. The refeeding period after extended fasting is revealed as one critical period of chromatin remodeling with convergent genomic changes. This genetic framework is a step toward harnessing hibernator adaptations in medicine.
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Affiliation(s)
- Elliott Ferris
- Departments of Neurobiology, University of Utah; Salt Lake City, 84105, USA
| | | | | | - Susan Steinwand
- Departments of Neurobiology, University of Utah; Salt Lake City, 84105, USA
| | | | - Dimitri Traenkner
- Departments of Neurobiology, University of Utah; Salt Lake City, 84105, USA
| | - Pablo J Maldonado-Catala
- Departments of Neurobiology, University of Utah; Salt Lake City, 84105, USA
- Biomedical Informatics, University of Utah; Salt Lake City, 84105, USA
| | - Christopher Gregg
- Departments of Neurobiology, University of Utah; Salt Lake City, 84105, USA
- Human Genetics, University of Utah; Salt Lake City, 84105, USA
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8
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Takase H, Hamanaka G, Hoshino T, Ohtomo R, Guo S, Mandeville ET, Lo EH, Arai K. Transcriptomic Profiling Reveals Neuroinflammation in the Corpus Callosum of a Transgenic Mouse Model of Alzheimer's Disease. J Alzheimers Dis 2024; 97:1421-1433. [PMID: 38277298 DOI: 10.3233/jad-231049] [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] [Indexed: 01/28/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive cognitive decline, affecting a significant portion of the aging population. While the cerebral cortex and hippocampus have been the primary focus of AD research, accumulating evidence suggests that white matter lesions in the brain, particularly in the corpus callosum, play an important role in the pathogenesis of the disease. OBJECTIVE This study aims to investigate the gene expression changes in the corpus callosum of 5xFAD transgenic mice, a widely used AD mouse model. METHODS We conducted behavioral tests for spatial learning and memory in 5xFAD transgenic mice and performed RNA sequencing analyses on the corpus callosum to examine transcriptomic changes. RESULTS Our results show cognitive decline and demyelination in the corpus callosum of 5xFAD transgenic mice. Transcriptomic analysis reveals a predominance of upregulated genes in AD mice, particularly those associated with immune cells, including microglia. Conversely, downregulation of genes related to chaperone function and clock genes such as Per1, Per2, and Cry1 is also observed. CONCLUSIONS This study suggests that activation of neuroinflammation, disruption of chaperone function, and circadian dysfunction are involved in the pathogenesis of white matter lesions in AD. The findings provide insights into potential therapeutic targets and highlight the importance of addressing white matter pathology and circadian dysfunction in AD treatment strategies.
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Affiliation(s)
- Hajime Takase
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
- YCU Center for Novel and Exploratory Clinical Trials (Y-NEXT), Yokohama City University Hospital, Yokohama, Japan
- Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Gen Hamanaka
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Tomonori Hoshino
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Ryo Ohtomo
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Shuzhen Guo
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Emiri T Mandeville
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Eng H Lo
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Ken Arai
- Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
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9
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Jiang Y, MacNeil LT. Simple model systems reveal conserved mechanisms of Alzheimer's disease and related tauopathies. Mol Neurodegener 2023; 18:82. [PMID: 37950311 PMCID: PMC10638731 DOI: 10.1186/s13024-023-00664-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 10/04/2023] [Indexed: 11/12/2023] Open
Abstract
The lack of effective therapies that slow the progression of Alzheimer's disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular pathways regulating proteostasis and stress response in these organisms facilitates the study of genetic factors that contribute to, or protect against, neurodegeneration. Here, we review genetic modifiers of neurodegeneration and related cellular pathways identified in the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, focusing on models of AD and related tauopathies. We further address the potential of simple model systems to better understand the fundamental mechanisms that lead to AD and other neurodegenerative disorders.
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Affiliation(s)
- Yuwei Jiang
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
| | - Lesley T MacNeil
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada.
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada.
- Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada.
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10
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Davletshin AI, Matveeva AA, Poletaeva II, Evgen'ev MB, Garbuz DG. The role of molecular chaperones in the mechanisms of epileptogenesis. Cell Stress Chaperones 2023; 28:599-619. [PMID: 37755620 PMCID: PMC10746656 DOI: 10.1007/s12192-023-01378-1] [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: 07/17/2023] [Revised: 08/30/2023] [Accepted: 09/08/2023] [Indexed: 09/28/2023] Open
Abstract
Epilepsy is a group of neurological diseases which requires significant economic costs for the treatment and care of patients. The central point of epileptogenesis stems from the failure of synaptic signal transmission mechanisms, leading to excessive synchronous excitation of neurons and characteristic epileptic electroencephalogram activity, in typical cases being manifested as seizures and loss of consciousness. The causes of epilepsy are extremely diverse, which is one of the reasons for the complexity of selecting a treatment regimen for each individual case and the high frequency of pharmacoresistant cases. Therefore, the search for new drugs and methods of epilepsy treatment requires an advanced study of the molecular mechanisms of epileptogenesis. In this regard, the investigation of molecular chaperones as potential mediators of epileptogenesis seems promising because the chaperones are involved in the processing and regulation of the activity of many key proteins directly responsible for the generation of abnormal neuronal excitation in epilepsy. In this review, we try to systematize current data on the role of molecular chaperones in epileptogenesis and discuss the prospects for the use of chemical modulators of various chaperone groups' activity as promising antiepileptic drugs.
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Affiliation(s)
| | - Anna A Matveeva
- Engelhardt Institute of Molecular Biology RAS, 119991, Moscow, Russia
- Moscow Institute of Physics and Technology, 141700, Dolgoprudny, Moscow Region, Russia
| | - Inga I Poletaeva
- Biology Department, Lomonosov Moscow State University, 119991, Moscow, Russia
| | | | - David G Garbuz
- Engelhardt Institute of Molecular Biology RAS, 119991, Moscow, Russia
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11
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Caruso G, Scalisi EM, Pecoraro R, Cardaci V, Privitera A, Truglio E, Capparucci F, Jarosova R, Salvaggio A, Caraci F, Brundo MV. Effects of carnosine on the embryonic development and TiO 2 nanoparticles-induced oxidative stress on Zebrafish. Front Vet Sci 2023; 10:1148766. [PMID: 37035814 PMCID: PMC10078361 DOI: 10.3389/fvets.2023.1148766] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/07/2023] [Indexed: 04/11/2023] Open
Abstract
Oxidative stress is due to an unbalance between pro-oxidants, such as reactive oxygen (ROS) and nitrogen (RNS) species, and antioxidants/antioxidant system. Under physiological conditions these species are involved in different cellular processes such as cellular homeostasis and immune response, while an excessive production of ROS/RNS has been linked to the development of various diseases such as cancer, diabetes, and Alzheimer's disease. In this context, the naturally occurring dipeptide carnosine has shown the ability to scavenge ROS, counteract lipid peroxidation, and inhibit proteins oxidation. Titanium dioxide nanoparticles (TiO2-NPs) have been widely used to produce cosmetics, in wastewater treatment, in food industry, and in healthcare product. As consequence, these NPs are often released into aquatic environments. The Danio rerio (commonly called zebrafish) embryos exposure to TiO2-NPs did not affect the hatching rate, but induced oxidative stress. According to this scenario, in the present study, we first investigated the effects of carnosine exposure and of a sub-toxic administration of TiO2-NPs on the development and survival of zebrafish embryos/larvae measured through the acute embryo toxicity test (FET-Test). Zebrafish larvae represent a useful model to study oxidative stress-linked disorders and to test antioxidant molecules, while carnosine was selected based on its well-known multimodal mechanism of action that includes a strong antioxidant activity. Once the basal effects of carnosine were assessed, we then evaluated its effects on TiO2-NPs-induced oxidative stress in zebrafish larvae, measured in terms of total ROS production (measured with 2,7-dichlorodihydrofluorescein diacetate probe) and protein expression by immunohistochemistry of two cellular stress markers, 70 kDa-heat shock protein (Hsp70) and metallothioneins (MTs). We demonstrated that carnosine did not alter the phenotypes of both embryos and larvae of zebrafish at different hours post fertilization. Carnosine was instead able to significantly decrease the enhancement of ROS levels in zebrafish larvae exposed to TiO2-NPs and its antioxidant effect was paralleled by the rescue of the protein expression levels of Hsp70 and MTs. Our results suggest a therapeutic potential of carnosine as a new pharmacological tool in the context of pathologies characterized by oxidative stress such as neurodegenerative disorders.
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Affiliation(s)
- Giuseppe Caruso
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, Troina, Italy
| | - Elena Maria Scalisi
- Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
| | - Roberta Pecoraro
- Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
| | - Vincenzo Cardaci
- Vita-Salute San Raffaele University, Milan, Italy
- Scuola Superiore di Catania, University of Catania, Catania, Italy
| | - Anna Privitera
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Emanuela Truglio
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
| | - Fabiano Capparucci
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Romana Jarosova
- Department of Chemistry and R.N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS, United States
| | | | - Filippo Caraci
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, Troina, Italy
| | - Maria Violetta Brundo
- Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
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12
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Lim SM, Nahm M, Kim SH. Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases. J Clin Neurol 2023; 19:101-114. [PMID: 36854331 PMCID: PMC9982182 DOI: 10.3988/jcn.2022.0379] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 03/02/2023] Open
Abstract
The cellular homeostasis of proteins (proteostasis) and RNA metabolism (ribostasis) are essential for maintaining both the structure and function of the brain. However, aging, cellular stress conditions, and genetic contributions cause disturbances in proteostasis and ribostasis that lead to protein misfolding, insoluble aggregate deposition, and abnormal ribonucleoprotein granule dynamics. In addition to neurons being primarily postmitotic, nondividing cells, they are more susceptible to the persistent accumulation of abnormal aggregates. Indeed, defects associated with the failure to maintain proteostasis and ribostasis are common pathogenic components of age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, the neuronal deposition of misfolded and aggregated proteins can cause both increased toxicity and impaired physiological function, which lead to neuronal dysfunction and cell death. There is recent evidence that irreversible liquid-liquid phase separation (LLPS) is responsible for the pathogenic aggregate formation of disease-related proteins, including tau, α-synuclein, and RNA-binding proteins, including transactive response DNA-binding protein 43, fused in sarcoma, and heterogeneous nuclear ribonucleoprotein A1. Investigations of LLPS and its control therefore suggest that chaperone/disaggregase, which reverse protein aggregation, are valuable therapeutic targets for effective treatments for neurological diseases. Here we review and discuss recent studies to highlight the importance of understanding the common cell death mechanisms of proteostasis and ribostasis in neurodegenerative diseases.
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Affiliation(s)
- Su Min Lim
- Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea
| | - Minyeop Nahm
- Dementia Research Group, Korea Brain Research Institute, Daegu, Korea
| | - Seung Hyun Kim
- Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
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13
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HSP70 mediates a crosstalk between the estrogen and the heat shock response pathways. J Biol Chem 2023; 299:102872. [PMID: 36610605 PMCID: PMC9926311 DOI: 10.1016/j.jbc.2023.102872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 12/24/2022] [Accepted: 12/27/2022] [Indexed: 01/06/2023] Open
Abstract
Cells respond to multiple signals from the environment simultaneously, which often creates crosstalk between pathways affecting the capacity to adapt to the changing environment. Chaperones are an important component in the cellular integration of multiple responses to environmental signals, often implicated in negative feedback and inactivation mechanisms. These mechanisms include the stabilization of steroid hormone nuclear receptors in the cytoplasm in the absence of their ligand. Here, we show using immunofluorescence, chromatin immunoprecipitation, and nascent transcripts production that the heat shock protein 70 (HSP70) chaperone plays a central role in a new crosstalk mechanism between the steroid and heat shock response pathways. HSP70-dependent feedback mechanisms are required to inactivate the heat shock factor 1 (HSF1) after activation. Interestingly, a steroid stimulation leads to faster accumulation of HSF1 in inactive foci following heat shock. Our results further show that in the presence of estrogen, HSP70 accumulates at HSF1-regulated noncoding regions, leading to deactivation of HSF1 and the abrogation of the heat shock transcriptional response. Using an HSP70 inhibitor, we demonstrate that the crosstalk between both pathways is dependent on the chaperone activity. These results suggest that HSP70 availability is a key determinant in the transcriptional integration of multiple external signals. Overall, these results offer a better understanding of the crosstalk between the heat shock and steroid responses, which are salient in neurodegenerative disorders and cancers.
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14
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Bartolo ND, Mortimer N, Manter MA, Sanchez N, Riley M, O'Malley TT, Hooker JM. Identification and Prioritization of PET Neuroimaging Targets for Microglial Phenotypes Associated with Microglial Activity in Alzheimer's Disease. ACS Chem Neurosci 2022; 13:3641-3660. [PMID: 36473177 DOI: 10.1021/acschemneuro.2c00607] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Activation of microglial cells accompanies the progression of many neurodegenerative disorders, including Alzheimer's disease (AD). Development of molecular imaging tools specific to microglia can help elucidate the mechanism through which microglia contribute to the pathogenesis and progression of neurodegenerative disorders. Through analysis of published genetic, transcriptomic, and proteomic data sets, we identified 19 genes with microglia-specific expression that we then ranked based on association with the AD characteristics, change in expression, and potential druggability of the target. We believe that the process we used to identify and rank microglia-specific genes is broadly applicable to the identification and evaluation of targets in other disease areas and for applications beyond molecular imaging.
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Affiliation(s)
- Nicole D Bartolo
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Niall Mortimer
- Human Biology and Data Science, Eisai Center for Genetics Guided Dementia Discovery, 35 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States
| | - Mariah A Manter
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Nicholas Sanchez
- Human Biology and Data Science, Eisai Center for Genetics Guided Dementia Discovery, 35 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States
| | - Misha Riley
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Tiernan T O'Malley
- Human Biology and Data Science, Eisai Center for Genetics Guided Dementia Discovery, 35 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States
| | - Jacob M Hooker
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
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15
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Dong Y, Li T, Ma Z, Zhou C, Wang X, Li J. HSPA1A, HSPA2, and HSPA8 Are Potential Molecular Biomarkers for Prognosis among HSP70 Family in Alzheimer's Disease. DISEASE MARKERS 2022; 2022:9480398. [PMID: 36246562 PMCID: PMC9553556 DOI: 10.1155/2022/9480398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 08/24/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022]
Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disease, which leads to impairment of cognition and memory. The heat shock protein 70 (HSP70) family plays an important role in the pathogenesis of AD. It is known to regulate protein misfolding in a variety of diseases, including inhibition of Aβ aggregation and NFT formation in AD. As yet, the diagnostic molecular markers of AD remain unclear. Herein, we sought to investigate molecular markers of HSP70 family that can affect diagnosis and treatment in AD through computational analysis. In this study, the intersection between HSP70 family members and immune molecules was taken to screen immune-related HSP70 family genes. Based on the datasets from the NCBI-Gene Expression Omnibus (GEO) database, we found that the expression levels of HSPA1A and HSPA2 were significantly increased in AD samples, while HSPA8 significantly decreased. Surprisingly, the combination of the 3 hub genes had a good diagnosis of AD via receiver operating characteristic curve (ROC). Moreover, the clinical value of the 3 hub genes was further assessed by the Spearman correlation analysis with AD-related genes, β-secretase activity, and γ-secretase activity. In terms of immune cell infiltration, we showed that the distribution of seven immune cell types (macrophages M2, neutrophils, T cells CD4 memory activated, macrophages M0, NK cells activated, plasma cells, and T cells follicular helper) was associated with the occurrence of AD by CIBERSORT. Furthermore, our data suggested that EP300, MYC, TP53, JUN, CREBBP, and ESR1 might be key transcription factors (TFs) for the 3 hub genes. In general, these findings suggest that HSPA1A, HSPA2, and HSPA8 are potential molecular biomarkers for prognosis among HSP70 family in AD, and it provides a new perspective on diagnostic and therapeutic targets for AD.
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Affiliation(s)
- Yeqing Dong
- Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Tongxin Li
- Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Zhonghui Ma
- Department of Laboratory Medicine, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Chi Zhou
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Xinxu Wang
- Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin 300222, China
| | - Jie Li
- Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin 300222, China
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16
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Beretta G, Shala AL. Impact of Heat Shock Proteins in Neurodegeneration: Possible Therapeutical Targets. Ann Neurosci 2022; 29:71-82. [PMID: 35875428 PMCID: PMC9305912 DOI: 10.1177/09727531211070528] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/24/2021] [Indexed: 01/20/2023] Open
Abstract
Human neurodegenerative diseases occur as a result of various factors. Regardless of the variety in the etiology of development, many of these diseases are characterized by the accumulation of pathological, misfolded proteins; hence, such diseases are considered as proteinopathies. While plenty of research study has been conducted in order to identify the pathophysiology of these proteinopathies, there is still a lack of understanding in terms of potential therapeutic targets. Molecular chaperones present the main workforce for cellular protection and stress response. Therefore, considering these functions, molecular chaperones present a promising target for research within the field of conformational diseases that arise from proteinopathies. Since the association between neurodegenerative disorders and their long-term consequences is well documented, the need for the development of new therapeutic strategies becomes even more critical. In this review, we summarized the molecular function of heat shock proteins and recent progress on their role, involvement, and other mechanisms related to neurodegeneration caused by different etiological factors. Based on the relevant scientific data, we will highlight the functional classification of heat shock proteins, regulatin, and their therapeutic potential for neurodegenerative disorders.
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Affiliation(s)
- Giangiacomo Beretta
- Department of Environmental Science and Policy, University of Milan, Milan, Italy
| | - Aida Loshaj Shala
- Department of Pharmacy, Faculty of Medicine, University Hasan Prishtina, Pristina, Kosovo
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17
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Effects of DISC1 on Alzheimer's disease cell models assessed by iTRAQ proteomics analysis. Biosci Rep 2022; 42:230594. [PMID: 34981809 PMCID: PMC8753346 DOI: 10.1042/bsr20211150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 11/17/2022] Open
Abstract
Alzheimer’s disease (AD) is a form of neurodegenerative disease in the elderly with no cure at present. In a previous study, we found that the scaffold protein, disrupted in Schizophrenia 1 (DISC1) is down-regulated in the AD brains, and ectopic expression of DISC1 can delay the progression of AD by protecting synaptic plasticity and down-regulating BACE1. However, the underlying mechanisms remain not to be elucidated. In the present study, we compared the proteomes of normal and DISC1high AD cells expressing the amyloid precursor protein (APP) using isobaric tag for relative and absolute quantitation (iTRAQ) and mass spectrometry (MS). The differentially expressed proteins (DEPs) were identified, and the protein–protein interaction (PPI) network was constructed to identify the interacting partners of DISC1. Based on the interaction scores, NDE1, GRM3, PTGER3 and KATNA1 were identified as functionally or physically related to DISC1, and may therefore regulate AD development. The DEPs were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases with the DAVID software, and the Non-supervised Orthologous Groups (eggNOG) database was used to determine their evolutionary relationships. The DEPs were significantly enriched in microtubules and mitochondria-related pathways. Gene set enrichment analysis (GSEA) was performed to identify genes and pathways that are activated when DISC1 is overexpressed. Our findings provide novel insights into the regulatory mechanisms underlying DISC1 function in AD.
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18
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Querfurth H, Marshall J, Parang K, Rioult-Pedotti MS, Tiwari R, Kwon B, Reisinger S, Lee HK. A PDK-1 allosteric agonist neutralizes insulin signaling derangements and beta-amyloid toxicity in neuronal cells and in vitro. PLoS One 2022; 17:e0261696. [PMID: 35061720 PMCID: PMC8782417 DOI: 10.1371/journal.pone.0261696] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 12/08/2021] [Indexed: 01/09/2023] Open
Abstract
The Alzheimer's brain is affected by multiple pathophysiological processes, which include a unique, organ-specific form of insulin resistance that begins early in its course. An additional complexity arises from the four-fold risk of Alzheimer's Disease (AD) in type 2 diabetics, however there is no definitive proof of causation. Several strategies to improve brain insulin signaling have been proposed and some have been clinically tested. We report findings on a small allosteric molecule that reverses several indices of insulin insensitivity in both cell culture and in vitro models of AD that emphasize the intracellular accumulation of β-amyloid (Aβi). PS48, a chlorophenyl pentenoic acid, is an allosteric activator of PDK-1, which is an Akt-kinase in the insulin/PI3K pathway. PS48 was active at 10 nM to 1 μM in restoring normal insulin-dependent Akt activation and in mitigating Aβi peptide toxicity. Synaptic plasticity (LTP) in prefrontal cortical slices from normal rat exposed to Aβ oligomers also benefited from PS48. During these experiments, neither overstimulation of PI3K/Akt signaling nor toxic effects on cells was observed. Another neurotoxicity model producing insulin insensitivity, utilizing palmitic acid, also responded to PS48 treatment, thus validating the target and indicating that its therapeutic potential may extend outside of β-amyloid reliance. The described in vitro and cell based-in vitro coupled enzymatic assay systems proved suitable platforms to screen a preliminary library of new analogs.
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Affiliation(s)
- Henry Querfurth
- Department of Neurology, Tufts Medical Center, Boston, MA, United States of America
| | - John Marshall
- Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, United States of America
| | - Keykavous Parang
- Center for Targeted Drug Delivery, Chapman University, School of Pharmacology, Irvine, CA United States of America
| | - Mengia S. Rioult-Pedotti
- Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, United States of America
- Department of Neurology, Clinical Neurorehabilitation, University of Zurich, Zurich, Switzerland
| | - Rakesh Tiwari
- Center for Targeted Drug Delivery, Chapman University, School of Pharmacology, Irvine, CA United States of America
| | - Bumsup Kwon
- Department of Neurology, Rhode Island Hospital, Providence, RI, United States of America
| | | | - Han-Kyu Lee
- Department of Neurology, Tufts Medical Center, Boston, MA, United States of America
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19
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Cheng L, Wang Y, Xiang L, Qi J. Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells. Biomedicines 2021; 9:biomedicines9101483. [PMID: 34680600 PMCID: PMC8533567 DOI: 10.3390/biomedicines9101483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 11/16/2022] Open
Abstract
Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from gentisides with a remarkable neuritogenic activity. However, the target of ABG-001 is yet to be defined to date. In this study, the potential target of ABG-001 was investigated via an activity-based protein profiling (ABPP) analysis, which is a chemical proteomic method for target identification by using chemical probes. Results indicated that the potential target proteins of ABG-001 were heat shock cognate 70 kDa protein (Hsc70), 78 kDa glucose-regulated protein (GRP78), and 14-3-3 theta protein. Then, the potential target of ABG-001 was confirmed by using inhibitors, the cellular thermal shift assay (CETSA) and small-interfering RNA (siRNA) analysis. The inhibitor of Hsc70 and siRNA significantly decreased the neurite outgrowth induced by ABG-001. Furthermore, ABG-001 induced neurite outgrowth was reduced by siRNA against Hsc70, and the results of CETSA suggested that Hsc70 showed a significant thermal stability-shifted effect upon ABG-001 treatment. These results indicated that Hsc70 is the target protein of ABG-001 in PC12 cells.
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Affiliation(s)
| | | | - Lan Xiang
- Correspondence: (L.X.); (J.Q.); Tel./Fax: +86-571-8820-8627 (L.X. & J.Q.)
| | - Jianhua Qi
- Correspondence: (L.X.); (J.Q.); Tel./Fax: +86-571-8820-8627 (L.X. & J.Q.)
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20
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Singh R, Kaur N, Dhingra N, Kaur T. Protein misfolding, ER Stress and Chaperones: An approach to develop chaperone-based therapeutics for Alzheimer's Disease. Int J Neurosci 2021:1-21. [PMID: 34402740 DOI: 10.1080/00207454.2021.1968859] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder with complex etiology that eventually leads to dementia. The main culprit of AD is the extracellular deposition of β-amyloid (Aβ) and intracellular neurofibrillary tangles. The protein conformational change and protein misfolding are the key events of AD pathophysiology, therefore endoplasmic reticulum (ER) stress is an apparent consequence. ER, stress-induced unfolded protein response (UPR) mediators (viz. PERK, IRE1, and ATF6) have been reported widely in the AD brain. Considering these factors, preventing proteins misfolding or aggregation of tau or amyloidogenic proteins appears to be the best approach to halt its pathogenesis. Therefore, therapies through chemical and pharmacological chaperones came to light as an alternative for the treatment of AD. Diverse studies have demonstrated 4-phenylbutyric acid (4-PBA) as a potential therapeutic agent in AD. The current review outlined the mechanism of protein misfolding, different etiological features behind the progression of AD, the significance of ER stress in AD, and the potential therapeutic role of different chaperones to counter AD. The study also highlights the gaps in current knowledge of the chaperones-based therapeutic approach and the possibility of developing chaperones as a potential therapeutic agent for AD treatment.
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Affiliation(s)
- Rimaljot Singh
- Department of Biophysics, Panjab University Chandigarh, India
| | - Navpreet Kaur
- Department of Biophysics, Panjab University Chandigarh, India
| | - Neelima Dhingra
- University Institute of Pharmaceutical Sciences, Panjab University Chandigarh, India
| | - Tanzeer Kaur
- Department of Biophysics, Panjab University Chandigarh, India
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21
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Kim KY, Shin KY, Chang KA. Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer's Disease: A Systematic Review and Meta-Analysis. Biomolecules 2021; 11:biom11070980. [PMID: 34356604 PMCID: PMC8301985 DOI: 10.3390/biom11070980] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/16/2021] [Accepted: 06/29/2021] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595-2.474), total-tau (SMD = 1.224, 95% CI: 0.534-1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795-4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.
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Affiliation(s)
- Ka Young Kim
- Department of Nursing, College of Nursing, Gachon University, Incheon 21936, Korea;
- Neuroscience Research Institute, Gachon University, Incheon 21565, Korea
| | - Ki Young Shin
- Bio-MAX Institute, Seoul National University, Seoul 08826, Korea
- Correspondence: (K.Y.S.); (K.-AC.); Tel.: +82-2-880-1737 (K.Y.S.); +82-32-899-6411 (K.-AC.)
| | - Keun-A Chang
- Neuroscience Research Institute, Gachon University, Incheon 21565, Korea
- Department of Pharmacology, College of Medicine, Gachon University, Incheon 21936, Korea
- Neuroscience of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon 21936, Korea
- Correspondence: (K.Y.S.); (K.-AC.); Tel.: +82-2-880-1737 (K.Y.S.); +82-32-899-6411 (K.-AC.)
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22
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Tiefensee Ribeiro C, Peixoto DO, Santos L, Saibro-Girardi C, Brum PO, Carazza-Kessler FG, Somensi N, Behrens LMP, Bittencourt RR, Soares LS, Silveira AK, de Oliveira J, Moreira JCF, Gasparotto J, Gelain DP. Intranasal HSP70 administration protects against dopaminergic denervation and modulates neuroinflammatory response in the 6-OHDA rat model. Brain Behav Immun Health 2021; 14:100253. [PMID: 34589762 PMCID: PMC8474599 DOI: 10.1016/j.bbih.2021.100253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/22/2021] [Accepted: 03/28/2021] [Indexed: 11/17/2022] Open
Abstract
HSP70 is one of the main molecular chaperones involved in the cellular stress response. Besides its chaperone action, HSP70 also modulates the immune response. Increased susceptibility to toxic insults in intra- and extracellular environments has been associated with insufficient amounts of inducible HSP70 in adult neurons. On the other hand, exogenous HSP70 administration has demonstrated neuroprotective effects in experimental models of age-related disorders. In this regard, this study investigated the effects of exogenous HSP70 in an animal model of dopaminergic denervation of the nigrostriatal axis. After unilateral intrastriatal injection with 6-hydroxydopamine (6-OHDA), the animals received purified recombinant HSP70 through intranasal administration (2 μg/rat/day) for 15 days. Our results indicate a neuroprotective effect of intranasal HSP70 against dopaminergic denervation induced by 6-OHDA. Exogenous HSP70 improved motor impairment and reduced the loss of dopaminergic neurons caused by 6-OHDA. Moreover, HSP70 modulated neuroinflammatory response in the substantia nigra, an important event in Parkinson's disease pathogenesis. Specifically, HSP70 treatment reduced microglial activation and astrogliosis induced by 6-OHDA, as well as IL-1β mRNA expression in this region. Also, recombinant HSP70 increased the protein content of HSP70 in the substantia nigra of rats that received 6-OHDA. These data suggest the neuroprotection of HSP70 against dopaminergic neurons damage after cellular stress. Finally, our results indicate that HSP70 neuroprotective action against 6-OHDA toxicity is related to inflammatory response modulation.
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Affiliation(s)
- Camila Tiefensee Ribeiro
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Daniel Oppermann Peixoto
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Lucas Santos
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Carolina Saibro-Girardi
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Pedro Ozorio Brum
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Flávio Gabriel Carazza-Kessler
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Nauana Somensi
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Luiza Marques Prates Behrens
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Reykla Ramon Bittencourt
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Laíssa Santos Soares
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Alexandre Kleber Silveira
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Jade de Oliveira
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - José Cláudio Fonseca Moreira
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Juciano Gasparotto
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Daniel Pens Gelain
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Role of a Heat Shock Transcription Factor and the Major Heat Shock Protein Hsp70 in Memory Formation and Neuroprotection. Cells 2021; 10:cells10071638. [PMID: 34210082 PMCID: PMC8305005 DOI: 10.3390/cells10071638] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/18/2021] [Accepted: 06/25/2021] [Indexed: 12/23/2022] Open
Abstract
Heat shock proteins (Hsps) represent the most evolutionarily ancient, conserved, and universal system for protecting cells and the whole body from various types of stress. Among Hsps, the group of proteins with a molecular weight of 70 kDa (Hsp70) plays a particularly important role. These proteins are molecular chaperones that restore the native conformation of partially denatured proteins after exposure to proteotoxic forms of stress and are critical for the folding and intracellular trafficking of de novo synthesized proteins under normal conditions. Hsp70s are expressed at high levels in the central nervous system (CNS) of various animals and protect neurons from various types of stress, including heat shock, hypoxia, and toxins. Numerous molecular and behavioral studies have indicated that Hsp70s expressed in the CNS are important for memory formation. These proteins contribute to the folding and transport of synaptic proteins, modulate signaling cascades associated with synaptic activation, and participate in mechanisms of neurotransmitter release. In addition, HSF1, a transcription factor that is activated under stress conditions and mediates Hsps transcription, is also involved in the transcription of genes encoding many synaptic proteins, whose levels are increased in neurons under stress and during memory formation. Thus, stress activates the molecular mechanisms of memory formation, thereby allowing animals to better remember and later avoid potentially dangerous stimuli. Finally, Hsp70 has significant protective potential in neurodegenerative diseases. Increasing the level of endogenous Hsp70 synthesis or injecting exogenous Hsp70 reduces neurodegeneration, stimulates neurogenesis, and restores memory in animal models of ischemia and Alzheimer’s disease. These findings allow us to consider recombinant Hsp70 and/or Hsp70 pharmacological inducers as potential drugs for use in the treatment of ischemic injury and neurodegenerative disorders.
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24
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Hedgehog Signaling Modulates Glial Proteostasis and Lifespan. Cell Rep 2021; 30:2627-2643.e5. [PMID: 32101741 DOI: 10.1016/j.celrep.2020.02.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 11/11/2019] [Accepted: 01/31/2020] [Indexed: 12/18/2022] Open
Abstract
The conserved Hedgehog signaling pathway has well-established roles in development. However, its function during adulthood remains largely unknown. Here, we investigated whether the Hedgehog signaling pathway is active during adult life in Drosophila melanogaster, and we uncovered a protective function for Hedgehog signaling in coordinating correct proteostasis in glial cells. Adult-specific depletion of Hedgehog reduces lifespan, locomotor activity, and dopaminergic neuron integrity. Conversely, increased expression of Hedgehog extends lifespan and improves fitness. Moreover, Hedgehog pathway activation in glia rescues the lifespan and age-associated defects of hedgehog mutants. The Hedgehog pathway regulates downstream chaperones, whose overexpression in glial cells was sufficient to rescue the shortened lifespan and proteostasis defects of hedgehog mutants. Finally, we demonstrate the protective ability of Hedgehog signaling in a Drosophila Alzheimer's disease model expressing human amyloid beta in the glia. Overall, we propose that Hedgehog signaling is requisite for lifespan determination and correct proteostasis in glial cells.
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25
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Saikumar J, Byrns CN, Hemphill M, Meaney DF, Bonini NM. Dynamic neural and glial responses of a head-specific model for traumatic brain injury in Drosophila. Proc Natl Acad Sci U S A 2020; 117:17269-17277. [PMID: 32611818 PMCID: PMC7382229 DOI: 10.1073/pnas.2003909117] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Traumatic brain injury (TBI) is the strongest environmental risk factor for the accelerated development of neurodegenerative diseases. There are currently no therapeutics to address this due to lack of insight into mechanisms of injury progression, which are challenging to study in mammalian models. Here, we have developed and extensively characterized a head-specific approach to TBI in Drosophila, a powerful genetic system that shares many conserved genes and pathways with humans. The Drosophila TBI (dTBI) device inflicts mild, moderate, or severe brain trauma by precise compression of the head using a piezoelectric actuator. Head-injured animals display features characteristic of mammalian TBI, including severity-dependent ataxia, life span reduction, and brain degeneration. Severe dTBI is associated with cognitive decline and transient glial dysfunction, and stimulates antioxidant, proteasome, and chaperone activity. Moreover, genetic or environmental augmentation of the stress response protects from severe dTBI-induced brain degeneration and life span deficits. Together, these findings present a tunable, head-specific approach for TBI in Drosophila that recapitulates mammalian injury phenotypes and underscores the ability of the stress response to mitigate TBI-induced brain degeneration.
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Affiliation(s)
- Janani Saikumar
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104
| | - China N Byrns
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Matthew Hemphill
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
| | - David F Meaney
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104
| | - Nancy M Bonini
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104;
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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26
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Ali TFS, Taira N, Iwamaru K, Koga R, Kamo M, Radwan MO, Tateishi H, Kurosaki H, Abdel-Aziz M, Abuo-Rahma GEDAA, Beshr EAM, Otsuka M, Fujita M. HSP70 induction by bleomycin metal core analogs. Bioorg Med Chem Lett 2020; 30:127002. [PMID: 32044184 DOI: 10.1016/j.bmcl.2020.127002] [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: 11/14/2019] [Revised: 01/28/2020] [Accepted: 01/30/2020] [Indexed: 11/16/2022]
Abstract
Induction of heat shock protein 70 (HSP70) is known to be effective against various diseases. We are interested in HSP70 induction capability of an antitumor antibiotic bleomycin which produces oxidative stress by iron chelate formation and oxygen activation in a cell. The HSP70 induction activity of bleomycin and its six metal core analogs was examined, and a compound HPH-1Trt of 10 μM was found to induce this protein in a pheochromocytoma cell line and some T cell and monocytic cell lines. Its mechanism is increase of HSP70 mRNA, but higher concentration of this compound showed toxicity. Two new derivatives were then synthesized, and one of them named DHPH-1Trt was shown to have less toxicity and higher HSP70 induction activity. This study would lead to a clue for new HSP70 inducer clinically used in near future.
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Affiliation(s)
- Taha F S Ali
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Naomi Taira
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan
| | - Kana Iwamaru
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan
| | - Ryoko Koga
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan
| | - Masahiro Kamo
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan
| | - Mohamed O Radwan
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan
| | - Hiroshi Tateishi
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan
| | - Hiromasa Kurosaki
- College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya, Aichi 463-8521, Japan
| | - Mohamed Abdel-Aziz
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | | | - Eman A M Beshr
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Masami Otsuka
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan; Department of Drug Discovery, Science Farm Ltd., 1-7-30 Kuhonji, Chuo-ku, Kumamoto, Kumamoto 862-0976, Japan.
| | - Mikako Fujita
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan.
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27
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Madadi S, Schwarzenbach H, Saidijam M, Mahjub R, Soleimani M. Potential microRNA-related targets in clearance pathways of amyloid-β: novel therapeutic approach for the treatment of Alzheimer's disease. Cell Biosci 2019; 9:91. [PMID: 31749959 PMCID: PMC6852943 DOI: 10.1186/s13578-019-0354-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023] Open
Abstract
Imbalance between amyloid-beta (Aβ) peptide synthesis and clearance results in Aβ deregulation. Failure to clear these peptides appears to cause the development of Alzheimer's disease (AD). In recent years, microRNAs have become established key regulators of biological processes that relate among others to the development and progression of neurodegenerative diseases, such as AD. This review article gives an overview on microRNAs that are involved in the Aβ cascade and discusses their inhibitory impact on their target mRNAs whose products participate in Aβ clearance. Understanding of the mechanism of microRNA in the associated signal pathways could identify novel therapeutic targets for the treatment of AD.
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Affiliation(s)
- Soheil Madadi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Heidi Schwarzenbach
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Massoud Saidijam
- Department of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Reza Mahjub
- Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Meysam Soleimani
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
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28
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Cuanalo-Contreras K, Moreno-Gonzalez I. Natural Products as Modulators of the Proteostasis Machinery: Implications in Neurodegenerative Diseases. Int J Mol Sci 2019; 20:ijms20194666. [PMID: 31547084 PMCID: PMC6801507 DOI: 10.3390/ijms20194666] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/13/2019] [Accepted: 09/15/2019] [Indexed: 02/07/2023] Open
Abstract
Proteins play crucial and diverse roles within the cell. To exert their biological function they must fold to acquire an appropriate three-dimensional conformation. Once their function is fulfilled, they need to be properly degraded to hamper any possible damage. Protein homeostasis or proteostasis comprises a complex interconnected network that regulates different steps of the protein quality control, from synthesis and folding, to degradation. Due to the primary role of proteins in cellular function, the integrity of this network is critical to assure functionality and health across lifespan. Proteostasis failure has been reported in the context of aging and neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Therefore, targeting the proteostasis elements emerges as a promising neuroprotective therapeutic approach to prevent or ameliorate the progression of these disorders. A variety of natural products are known to be neuroprotective by protein homeostasis interaction. In this review, we will focus on the current knowledge regarding the use of natural products as modulators of different components of the proteostasis machinery within the framework of age-associated neurodegenerative diseases.
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Affiliation(s)
- Karina Cuanalo-Contreras
- The Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, The University of Texas Houston Health Science Center at Houston, Houston, TX 77030, USA.
| | - Ines Moreno-Gonzalez
- The Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, The University of Texas Houston Health Science Center at Houston, Houston, TX 77030, USA.
- Departamento Biologia Celular, Genetica y Fisiologia, Instituto de Investigacion Biomedica de Malaga-IBIMA, Facultad de Ciencias, Universidad de Malaga, 28031 Madrid, Spain.
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain.
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29
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Clarke BE, Gil RS, Yip J, Kalmar B, Greensmith L. Regional differences in the inflammatory and heat shock response in glia: implications for ALS. Cell Stress Chaperones 2019; 24:857-870. [PMID: 31168740 PMCID: PMC6717175 DOI: 10.1007/s12192-019-01005-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/03/2019] [Accepted: 05/04/2019] [Indexed: 12/11/2022] Open
Abstract
Preferential neuronal vulnerability is characteristic of several neurodegenerative diseases including the motor neuron disease amyotrophic lateral sclerosis (ALS). It is well established that glia play a critical role in ALS, but it is unknown whether regional differences in the ability of glia to support motor neurons contribute to the specific pattern of neuronal degeneration. In this study, using primary mixed glial cultures from different mouse CNS regions (spinal cord and cortex), we examined whether regional differences exist in key glial pathways that contribute to, or protect against, motor neuron degeneration. Specifically, we examined the NF-κB-mediated inflammatory pathway and the cytoprotective heat shock response (HSR). Glial cultures were treated with pro-inflammatory stimuli, tumour necrosis factor-ɑ/lipopolysaccharide or heat stressed to stimulate the inflammatory and HSR respectively. We found that spinal cord glia expressed more iNOS and produced more NO compared to cortical glia in response to inflammatory stimuli. Intriguingly, we found that expression of ALS-causing SOD1G93A did not elevate the levels of NO in spinal cord glia. However, activation of the stress-responsive HSR was attenuated in SOD1G93A cultures, with a reduced Hsp70 induction in response to stressful stimuli. Exposure of spinal cord glia to heat shock in combination with inflammatory stimuli reduced the activation of the inflammatory response. The results of this study suggest that impaired heat shock response in SOD1G93A glia may contribute to the exacerbated inflammatory reactions observed in ALS mice. Graphical abstract Mixed primary glial cultures were established from cortical and spinal cord regions of wild-type mice and mice expressing ALS-causing mutant human SOD1 and the inflammatory and heat shock responses were investigated in these cultures. In the absence of stress, all cultures appeared to have similar cellular composition, levels of inflammatory mediators and similar expression level of heat shock proteins. When stimulated, spinal cord glia were more reactive and activated the inflammatory pathway more readily than cortical glia; this response was similar in wild-type and SOD1G93A glial cultures. Although the heat shock response was similar in spinal cord and cortical glial, in SOD1G93A expressing glia from both the spinal cord and cortex, the induction of heat shock response was diminished. This impaired heat shock response in SOD1G93A glia may therefore contribute to the exacerbated inflammatory reactions observed in ALS mice.
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Affiliation(s)
- Benjamin E Clarke
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
- MRC Centre for Neuromuscular Disease, London, WC1N 3BG, UK
| | - Rebecca San Gil
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
- Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia
| | - Jing Yip
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
| | - Bernadett Kalmar
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK.
| | - Linda Greensmith
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
- MRC Centre for Neuromuscular Disease, London, WC1N 3BG, UK
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30
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Lyon MS, Milligan C. Extracellular heat shock proteins in neurodegenerative diseases: New perspectives. Neurosci Lett 2019; 711:134462. [PMID: 31476356 DOI: 10.1016/j.neulet.2019.134462] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 08/23/2019] [Accepted: 08/24/2019] [Indexed: 01/20/2023]
Abstract
One pathological hallmark of neurodegenerative diseases and CNS trauma is accumulation of insoluble, hydrophobic molecules and protein aggregations found both within and outside cells. These may be the consequences of an inadequate or overburdened cellular response to stresses resulting from potentially toxic changes in extra- and intracellular environments. The upregulated expression of heat shock proteins (HSPs) is one example of a highly conserved cellular response to both internal and external stress. Intracellularly these proteins act as chaperones, playing vital roles in the folding of nascent polypeptides, the translocation of proteins between subcellular locations, and the disaggregation of misfolded or aggregated proteins in an attempt to maintain cellular proteostasis during both homeostatic and stressful conditions. While the predominant study of the HSPs has focused on their intracellular chaperone functions, it remains unclear if all neuronal populations can mount a complete stress response. Alternately, it is now well established that some members of this family of proteins can be secreted by nearby, non-neuronal cells to act in the extracellular environment. This review addresses the current literature detailing the use of exogenous and extracellular HSPs in the treatment of cellular and animal models of neurodegenerative disease. These findings offer a new measure of therapeutic potential to the HSPs, but obstacles must be overcome before they can be efficiently used in a clinical setting.
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Affiliation(s)
- Miles S Lyon
- Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States
| | - Carol Milligan
- Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
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31
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Cuadrado-Tejedor M, Pérez-González M, García-Muñoz C, Muruzabal D, García-Barroso C, Rabal O, Segura V, Sánchez-Arias JA, Oyarzabal J, Garcia-Osta A. Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease. Front Aging Neurosci 2019; 11:149. [PMID: 31281249 PMCID: PMC6597953 DOI: 10.3389/fnagi.2019.00149] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 06/06/2019] [Indexed: 12/19/2022] Open
Abstract
The discouraging results with therapies for Alzheimer’s disease (AD) in clinical trials, highlights the urgent need to adopt new approaches. Like other complex diseases, it is becoming clear that AD therapies should focus on the simultaneous modulation of several targets implicated in the disease. Recently, using reference compounds and the first-in class CM-414, we demonstrated that the simultaneous inhibition of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore, CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695 ameliorates memory impairment and diminishes brain Aβ, although its therapeutic effect was no longer apparent 4 weeks after the treatment was interrupted. An increase in the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70 (Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic treatment with CM-695 appears to reverse the AD phenotype in a safe and effective manner. Taking into account that AD is a multifactorial disorder, the multimodal action of these compounds and the different events they affect may open new avenues to combat AD.
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Affiliation(s)
- Mar Cuadrado-Tejedor
- Neurobiology of Alzheimer's Disease, Neurosciences Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.,Health Research Institute of Navarra (IDISNA), Pamplona, Spain
| | - Marta Pérez-González
- Neurobiology of Alzheimer's Disease, Neurosciences Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.,Health Research Institute of Navarra (IDISNA), Pamplona, Spain
| | - Cristina García-Muñoz
- Neurobiology of Alzheimer's Disease, Neurosciences Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Damián Muruzabal
- Neurobiology of Alzheimer's Disease, Neurosciences Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Carolina García-Barroso
- Neurobiology of Alzheimer's Disease, Neurosciences Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Obdulia Rabal
- Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Víctor Segura
- Health Research Institute of Navarra (IDISNA), Pamplona, Spain.,Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Juan A Sánchez-Arias
- Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Julen Oyarzabal
- Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Ana Garcia-Osta
- Neurobiology of Alzheimer's Disease, Neurosciences Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Health Research Institute of Navarra (IDISNA), Pamplona, Spain
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32
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Garbuz DG, Zatsepina OG, Evgen’ev MB. The Major Human Stress Protein Hsp70 as a Factor of Protein Homeostasis and a Cytokine-Like Regulator. Mol Biol 2019. [DOI: 10.1134/s0026893319020055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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33
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Ghosh A, Gangadharan A, Verma M, Das S, Matai L, Dash DP, Dash D, Mapa K, Chakraborty K. Cellular responses to proteostasis perturbations reveal non-optimal feedback in chaperone networks. Cell Mol Life Sci 2019; 76:1605-1621. [PMID: 30683983 PMCID: PMC11105298 DOI: 10.1007/s00018-019-03013-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 01/10/2019] [Accepted: 01/15/2019] [Indexed: 11/30/2022]
Abstract
The proteostasis network (PN) comprises a plethora of proteins that are dedicated to aid in protein folding and maintenance; some with overlapping functions. Despite this, there are multiple pathophysiological states associated with depletion of chaperones. This is counter-intuitive, assuming cells have the ability to re-program transcriptional outputs in accordance with its proteostasic limitations. Here, we have used S. cerevisiae to understand how cells respond to different types of proteostasis impairments. We monitored the proteostasis status and transcriptome of single deletions of fourteen different Protein Quality Control (PQC) genes. In most cases, cellular response did not activate proteostasis components or pathways that could either complement the function of the missing PQC gene or restore proteostasis. Over-expression of alternate machineries could restore part of the proteostasis defect in two representative PQC gene deletion strains. We posit that S. cerevisiae inherently lacks the ability to sense and respond optimally to defects in proteostasis caused due to deletion of specific PQC components.
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Affiliation(s)
- Asmita Ghosh
- CSIR-Institute of Genomics and Integrative Biology, Delhi, 110025, India
- Academy of Scientific and Innovative Research, Coordination Office, CSIR-Human Resource Development Centre Campus, Ghaziabad, 201002, India
| | - Abhilash Gangadharan
- CSIR-Institute of Genomics and Integrative Biology, Delhi, 110025, India
- Academy of Scientific and Innovative Research, Coordination Office, CSIR-Human Resource Development Centre Campus, Ghaziabad, 201002, India
| | - Monika Verma
- CSIR-Institute of Genomics and Integrative Biology, Delhi, 110025, India
- Academy of Scientific and Innovative Research, Coordination Office, CSIR-Human Resource Development Centre Campus, Ghaziabad, 201002, India
| | - Sarada Das
- Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, 201314, India
| | - Latika Matai
- CSIR-Institute of Genomics and Integrative Biology, Delhi, 110025, India
- Academy of Scientific and Innovative Research, Coordination Office, CSIR-Human Resource Development Centre Campus, Ghaziabad, 201002, India
| | - Devi Prasanna Dash
- CSIR-Institute of Genomics and Integrative Biology, Delhi, 110025, India
- Academy of Scientific and Innovative Research, Coordination Office, CSIR-Human Resource Development Centre Campus, Ghaziabad, 201002, India
| | - Debasis Dash
- CSIR-Institute of Genomics and Integrative Biology, Delhi, 110025, India
- Academy of Scientific and Innovative Research, Coordination Office, CSIR-Human Resource Development Centre Campus, Ghaziabad, 201002, India
| | - Koyeli Mapa
- Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, 201314, India
| | - Kausik Chakraborty
- CSIR-Institute of Genomics and Integrative Biology, Delhi, 110025, India.
- Academy of Scientific and Innovative Research, Coordination Office, CSIR-Human Resource Development Centre Campus, Ghaziabad, 201002, India.
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34
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Joutsen J, Sistonen L. Tailoring of Proteostasis Networks with Heat Shock Factors. Cold Spring Harb Perspect Biol 2019; 11:cshperspect.a034066. [PMID: 30420555 DOI: 10.1101/cshperspect.a034066] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Heat shock factors (HSFs) are the main transcriptional regulators of the heat shock response and indispensable for maintaining cellular proteostasis. HSFs mediate their protective functions through diverse genetic programs, which are composed of genes encoding molecular chaperones and other genes crucial for cell survival. The mechanisms that are used to tailor HSF-driven proteostasis networks are not yet completely understood, but they likely comprise from distinct combinations of both genetic and proteomic determinants. In this review, we highlight the versatile HSF-mediated cellular functions that extend from cellular stress responses to various physiological and pathological processes, and we underline the key advancements that have been achieved in the field of HSF research during the last decade.
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Affiliation(s)
- Jenny Joutsen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, 20520 Turku, Finland.,Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Lea Sistonen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, 20520 Turku, Finland.,Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland
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35
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Rezvykh AP, Yurinskaya MM, Vinokurov MG, Krasnov GS, Mitkevich VA, Makarov AA, Evgen’ev MB, Zatsepina OG. The Effect of Beta-Amyloid Peptides and Main Stress Protein HSP70 on Human SH-SY5Y Neuroblastoma Proteome. Mol Biol 2018. [DOI: 10.1134/s0026893318060158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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36
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Marino Gammazza A, Restivo V, Baschi R, Caruso Bavisotto C, Cefalù AB, Accardi G, Conway de Macario E, Macario AJ, Cappello F, Monastero R. Circulating Molecular Chaperones in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Zabùt Aging Project. J Alzheimers Dis 2018; 87:161-172. [PMID: 30584145 PMCID: PMC9277667 DOI: 10.3233/jad-180825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Antonella Marino Gammazza
- Department of Biomedicine, Neuroscience and advanced Diagnostic, University of Palermo, Palermo, Italy
- Euro Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
| | - Vincenzo Restivo
- Department of Science for Health Promotion and Mother Science Health “G. D’Alessandro”, University of Palermo, Palermo, Italy
| | - Roberta Baschi
- Department of Biomedicine, Neuroscience and advanced Diagnostic, University of Palermo, Palermo, Italy
| | - Celeste Caruso Bavisotto
- Department of Biomedicine, Neuroscience and advanced Diagnostic, University of Palermo, Palermo, Italy
- Euro Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
- Institute of Biophysics, Section of Palermo, National Research Council, Palermo, Italy
| | - Angelo B. Cefalù
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Giulia Accardi
- Department of Biomedicine, Neuroscience and advanced Diagnostic, University of Palermo, Palermo, Italy
| | - Everly Conway de Macario
- Department of Microbiology and Immunology, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD, USA
| | - Alberto J.L. Macario
- Euro Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
- Department of Microbiology and Immunology, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD, USA
| | - Francesco Cappello
- Department of Biomedicine, Neuroscience and advanced Diagnostic, University of Palermo, Palermo, Italy
- Euro Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
| | - Roberto Monastero
- Department of Biomedicine, Neuroscience and advanced Diagnostic, University of Palermo, Palermo, Italy
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37
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Corpas R, Griñán-Ferré C, Rodríguez-Farré E, Pallàs M, Sanfeliu C. Resveratrol Induces Brain Resilience Against Alzheimer Neurodegeneration Through Proteostasis Enhancement. Mol Neurobiol 2018; 56:1502-1516. [DOI: 10.1007/s12035-018-1157-y] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 05/28/2018] [Indexed: 12/27/2022]
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38
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Lee S, Choi BR, Kim J, LaFerla FM, Park JHY, Han JS, Lee KW, Kim J. Sulforaphane Upregulates the Heat Shock Protein Co-Chaperone CHIP and Clears Amyloid-β and Tau in a Mouse Model of Alzheimer's Disease. Mol Nutr Food Res 2018; 62:e1800240. [PMID: 29714053 DOI: 10.1002/mnfr.201800240] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 04/17/2018] [Indexed: 11/08/2022]
Abstract
SCOPE Sulforaphane is an herbal isothiocyanate enriched in cruciferous vegetables. Here, the authors investigate whether sulforaphane modulates the production of amyloid-β (Aβ) and tau, the two main pathological factors in Alzheimer's disease (AD). METHODS AND RESULTS A triple transgenic mouse model of AD (3 × Tg-AD) is used to study the effect of sulforaphane. Oral gavage of sulforaphane reduces protein levels of monomeric and polymeric forms of Aβ as well as tau and phosphorylated tau in 3 × Tg-AD mice. However, sulforaphane treatment do not affect mRNA expression of amyloid precursor protein or tau. As previous studies show that Aβ and tau metabolism are influenced by a heat shock protein (HSP) co-chaperone, C-terminus of HSP70-interacting protein (CHIP), the authors examine whether sulforaphane can modulate CHIP. The authors find that sulforaphane treatment increase levels of CHIP and HSP70. Furthermore, observations of CHIP-deficient primary neurons derived from 3 × Tg-AD mice suggest that sulforaphane treatment increase CHIP level and clear the accumulation of Aβ and tau. Finally, sulforaphane ameliorated memory deficits in 3 × Tg-AD mice as reveal by novel object/location recognition tests and contextual fear conditioning tests. CONCLUSION These results demonstrate that sulforaphane treatment upregulates CHIP and has the potential to decrease the accumulation of Aβ and tau in patients with AD.
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Affiliation(s)
- Siyoung Lee
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Bo-Ryoung Choi
- Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea
| | - Jisung Kim
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Frank M LaFerla
- Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA 92697, USA
| | - Jung Han Yoon Park
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Jung-Soo Han
- Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea
| | - Ki Won Lee
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Jiyoung Kim
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Republic of Korea.,Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
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39
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Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides. Proc Natl Acad Sci U S A 2018; 115:E5008-E5017. [PMID: 29760078 PMCID: PMC5984528 DOI: 10.1073/pnas.1801989115] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Protein AMPylation in eukaryotes is a comparatively understudied posttranslational modification. With the exception of yeast, all eukaryotes have the enzymatic machinery required to execute this modification. Members of the heat shock protein family in different cellular compartments appear to be preferred targets for AMPylation, but it has proven challenging to adduce its biological function. We show that genetic modifications that affect AMPylation status, through generation of null alleles and a constitutively active version of the AMPylase FIC-1, can have a major impact on the susceptibility of Caenorhabditis elegans to neurodegenerative conditions linked to protein aggregation. Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation, a posttranslational protein modification that has emerged as a powerful modulator of HSP70 activity, influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in Caenorhabditis elegans directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)-extended polypeptide, and of α-synuclein (α-syn). Expression of a constitutively active C. elegans AMPylase FIC-1(E274G) under its own promoter expedites aggregation of Aβ and α-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Overexpression of FIC-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity in vivo. We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cytoprotective, rather than a cytotoxic, role for such protein aggregates.
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40
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Evgen'ev MB, Krasnov GS, Nesterova IV, Garbuz DG, Karpov VL, Morozov AV, Snezhkina AV, Samokhin AN, Sergeev A, Kulikov AM, Bobkova NV. Molecular Mechanisms Underlying Neuroprotective Effect of Intranasal Administration of Human Hsp70 in Mouse Model of Alzheimer's Disease. J Alzheimers Dis 2018; 59:1415-1426. [PMID: 28759972 DOI: 10.3233/jad-170398] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Heat shock protein 70, encoded by the HSPA1A gene in humans, is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during the course of aging and as a result of several neurodegenerative diseases. Herein, we investigated whether sub-chronic intranasal administration of exogenous Hsp70 (eHsp70) exerts a neuroprotective effect on the temporal cortex and areas of the hippocampus in transgenic 5XFAD mice, a model of Alzheimer's disease. The quantitative analysis of neuronal pathologies in the compared groups, transgenic (Tg) versus non-transgenic (nTg), revealed high level of abnormalities in the brains of transgenic mice. Treatment with human recombinant Hsp70 had profound rejuvenation effect on both neuronal morphology and functional state in the temporal cortex and hippocampal regions in transgenic mice. Hsp70 administration had a smaller, but still significant, effect on the functional state of neurons in non-transgenic mice as well. Using deep sequencing, we identified multiple differentially expressed genes (DEGs) in the hippocampus of transgenic and non-transgenic mice. Furthermore, this analysis demonstrated that eHsp70 administration strongly modulates the spectrum of DEGs in transgenic animals, reverting to a pattern similar to that observed in non-transgenic age-matched mice, which included upregulation of genes responsible for amine transport, transmission of nerve impulses and other pathways that are impaired in 5XFAD mice. Overall, our data indicate that Hsp70 treatment may be an effective therapeutic against old age diseases of the Alzheimer's type.
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Affiliation(s)
- Michail B Evgen'ev
- Engelhardt Institute of Molecular Biology, Moscow, Russia.,Institute of Cell Biophysics, RAS, Pushchino, Moscow region, Russia
| | | | - Inna V Nesterova
- Institute of Cell Biophysics, RAS, Pushchino, Moscow region, Russia
| | - David G Garbuz
- Engelhardt Institute of Molecular Biology, Moscow, Russia
| | - Vadim L Karpov
- Engelhardt Institute of Molecular Biology, Moscow, Russia
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41
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Katayama T, Uesugi K, Morishima K. Analytical Model and Experimental Evaluation of the Micro-Scale Thermal Property Sensor for Single-Sided Measurement. MICROMACHINES 2018; 9:mi9040168. [PMID: 30424101 PMCID: PMC6187662 DOI: 10.3390/mi9040168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 11/24/2022]
Abstract
We report a new analytical model of the MEMS-based thermal property sensor for samples which are difficult to handle and susceptible to damage by thermal stimulus, such as living cells. Many sensor designs had been reported for thermal property measurements, but only a few of them have considered the analytical model of the single-sided measurement in which a measurement sample is placed on the sensor substrate. Even in the few designs that have considered the analytical model, their applicable limits are restricted to more than 1 mm length in practical situations. Our new model considers both the sample and the sensor substrate thermal properties and is applicable to a sensor length less than 1 µm. In order to minimize the influence of the heat stimulus to the sample, the model formulates the required heat dissipating time for different sensor geometries. We propose fast and precise detection circuit architecture to realize our model, and we discuss the sensor performance for a number of different designs.
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Affiliation(s)
- Takashi Katayama
- Department of Mechanical Engineering, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Kaoru Uesugi
- Department of Mechanical Engineering, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Keisuke Morishima
- Department of Mechanical Engineering, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
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42
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Frinchi M, Scaduto P, Cappello F, Belluardo N, Mudò G. Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus. J Cell Physiol 2018; 233:6107-6116. [DOI: 10.1002/jcp.26454] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 12/04/2017] [Accepted: 01/02/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Monica Frinchi
- Department of Experimental Biomedicine and Clinical Neuroscienc es, div. of Human PhysiologyUniversity of PalermoPalermoItaly
| | - Pietro Scaduto
- Department of Experimental Biomedicine and Clinical Neuroscienc es, div. of Human PhysiologyUniversity of PalermoPalermoItaly
| | - Francesco Cappello
- Department of Experimental Biomedicine and Clinical Neurosciences, div. of AnatomyUniversity of PalermoPalermoItaly
- Euro‐Mediterranean Institute of Science and TechnologyPalermoItaly
- Department of BiologyTemple UniversityPhiladelphiaPennsylvania
| | - Natale Belluardo
- Department of Experimental Biomedicine and Clinical Neuroscienc es, div. of Human PhysiologyUniversity of PalermoPalermoItaly
| | - Giuseppa Mudò
- Department of Experimental Biomedicine and Clinical Neuroscienc es, div. of Human PhysiologyUniversity of PalermoPalermoItaly
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43
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Lee HK, Kwon B, Lemere CA, de la Monte S, Itamura K, Ha AY, Querfurth HW. mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. J Alzheimers Dis 2018; 56:1015-1036. [PMID: 28035937 DOI: 10.3233/jad-161029] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42, mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD.
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Affiliation(s)
- Han-Kyu Lee
- Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Bumsup Kwon
- Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Cynthia A Lemere
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Suzanne de la Monte
- Department of Pathology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Kyohei Itamura
- Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Austin Y Ha
- Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Henry W Querfurth
- Department of Neurology, Rhode Island Hospital and Brown University Warren Alpert Medical School, Providence, RI, USA
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44
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Boyko AA, Troyanova NI, Kovalenko EI, Sapozhnikov AM. Similarity and Differences in Inflammation-Related Characteristics of the Peripheral Immune System of Patients with Parkinson's and Alzheimer's Diseases. Int J Mol Sci 2017; 18:ijms18122633. [PMID: 29211044 PMCID: PMC5751236 DOI: 10.3390/ijms18122633] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 11/21/2017] [Accepted: 12/01/2017] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common age-related neurodegenerative disorders. Both diseases are characterized by chronic inflammation in the brain-neuroinflammation. The first signs of PD and AD are most often manifested in old age, in which the immune system is usually characterized by chronic inflammation, so-called "inflammaging" In recent years, there is growing evidence that pathogenesis of these diseases is connected with both regional and peripheral immune processes. Currently, the association of clinical signs of PD and AD with different characteristics of patient immune status is actively being researched. In this mini-review we compare the association of PD and AD alterations of a number of immune system parameters connected with the process of inflammation.
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Affiliation(s)
- Anna A Boyko
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
| | - Natalya I Troyanova
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
| | - Elena I Kovalenko
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
| | - Alexander M Sapozhnikov
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
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45
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Wang B, Liu Y, Huang L, Chen J, Li JJ, Wang R, Kim E, Justicia C, Sakata K, Chen H, Planas A, Ostrom RS, Li W, Yang G, McDonald MP, Chen R, Heck D, Liao FF, Liao FF. A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. Mol Psychiatry 2017; 22:990-1001. [PMID: 27457810 PMCID: PMC5323357 DOI: 10.1038/mp.2016.104] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 03/27/2016] [Accepted: 04/20/2016] [Indexed: 11/09/2022]
Abstract
Induction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited central nervous system permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat-shock-like response but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer's disease, without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (>3 days) nuclear activation of the heat-shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome.
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Affiliation(s)
- Bin Wang
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Yu Liu
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Lianyan Huang
- Department of Anesthesiology, New York University School of Medicine, New York, NY 10016
| | - Jianjun Chen
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Jing jing Li
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Ruishan Wang
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Eunhee Kim
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Carles Justicia
- Department of Brain Ischemia and Neurodegeneration, Institute for Biomedical Research (IIBB-CSIC), Rossello 161, planta 6, 08036-Barcelona, Spain
| | - Kazuko Sakata
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Hao Chen
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Anna Planas
- Department of Brain Ischemia and Neurodegeneration, Institute for Biomedical Research (IIBB-CSIC), Rossello 161, planta 6, 08036-Barcelona, Spain
| | - Rennolds S Ostrom
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Wei Li
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Guang Yang
- Department of Anesthesiology, New York University School of Medicine, New York, NY 10016
| | - Michael P. McDonald
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163,Department of Neurology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Ruihong Chen
- Oncosynergy, Inc; 409 Illinois St., San Francisco, CA, 94158
| | - Detlef Heck
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163
| | - Francesca-Fang Liao
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163,Correspondence should be addressed to Francesca-Fang Liao, Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163.
| | - F-F Liao
- Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA
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46
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De Mena L, Chhangani D, Fernandez-Funez P, Rincon-Limas DE. secHsp70 as a tool to approach amyloid-β42 and other extracellular amyloids. Fly (Austin) 2017; 11:179-184. [PMID: 28165856 PMCID: PMC5552267 DOI: 10.1080/19336934.2017.1291104] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Self-association of amyloidogenic proteins is the main pathological trigger in a wide variety of neurodegenerative disorders. These aggregates are deposited inside or outside the cell due to hereditary mutations, environmental exposures or even normal aging. Cumulative evidence indicates that the heat shock chaperone Hsp70 possesses robust neuroprotection against various intracellular amyloids in Drosophila and mouse models. However, its protective role against extracellular amyloids was largely unknown as its presence outside the cells is very limited. Our recent manuscript in PNAS revealed that an engineered form of secreted Hsp70 (secHsp70) is highly protective against toxicity induced by extracellular deposition of the amyloid-β42 (Aβ42) peptide. In this Extra View article, we extend our analysis to other members of the heat shock protein family. We created PhiC31-based transgenic lines for human Hsp27, Hsp40, Hsp60 and Hsp70 and compared their activities in parallel against extracellular Aβ42. Strikingly, only secreted Hsp70 exhibits robust protection against Aβ42-triggered toxicity in the extracellular milieu. These observations indicate that the ability of secHsp70 to suppress Aβ42 insults is quite unique and suggest that targeted secretion of Hsp70 may represent a new therapeutic approach against Aβ42 and other extracellular amyloids. The potential applications of this engineered chaperone are discussed.
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Affiliation(s)
- Lorena De Mena
- a Department of Neurology , McKnight Brain Institute University of Florida , Gainesville , FL , USA
| | - Deepak Chhangani
- a Department of Neurology , McKnight Brain Institute University of Florida , Gainesville , FL , USA
| | - Pedro Fernandez-Funez
- b Department of Biomedical Sciences , University of Minnesota Medical School , Duluth , MN , USA
| | - Diego E Rincon-Limas
- a Department of Neurology , McKnight Brain Institute University of Florida , Gainesville , FL , USA.,c Department of Neuroscience, Genetics Institute and Center for Translational Research in Neurodegenerative Disease , University of Florida , Gainesville , FL , USA
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Yi-Zhi-Fang-Dai Formula Protects against A β1-42 Oligomer Induced Cell Damage via Increasing Hsp70 and Grp78 Expression in SH-SY5Y Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:8591656. [PMID: 27829867 PMCID: PMC5086516 DOI: 10.1155/2016/8591656] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 08/25/2016] [Accepted: 09/15/2016] [Indexed: 11/19/2022]
Abstract
Yi-Zhi-Fang-Dai formula (YZFDF) is an experiential prescription used to cure dementia cases like Alzheimer's disease (AD). In this study, the main effective compounds of YZFDF have been identified from this formula, and the neuroprotective effect against Aβ1–42 oligomer of YZFDF has been tested in SH-SY5Y cells. Our results showed that YZFDF could increase cell viability and could attenuate endothelial reticula- (ER-) mediated apoptosis. Evidence indicated that protein folding and endothelial reticula stress (ERS) played an important role in the AD pathological mechanism. We further explored the expression of Hsp70, an important molecular chaperon facilitating the folding of other proteins, and Grp78, the marker protein of ERS in SH-SY5Y cells. Data told us that YZFDF pretreatment could influence the mRNA and protein expression of these two proteins. At last, we also found that YZFDF pretreatment could activate Akt in SH-SY5Y cells. All these above indicate that YZFDF could be a potent therapeutic candidate for AD treatment.
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Leite JSM, Cruzat VF, Krause M, Homem de Bittencourt PI. Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions. ACTA ACUST UNITED AC 2016. [DOI: 10.1186/s41110-016-0021-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Su KH, Dai C. Metabolic control of the proteotoxic stress response: implications in diabetes mellitus and neurodegenerative disorders. Cell Mol Life Sci 2016; 73:4231-4248. [PMID: 27289378 PMCID: PMC5599143 DOI: 10.1007/s00018-016-2291-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 05/13/2016] [Accepted: 06/07/2016] [Indexed: 12/12/2022]
Abstract
Proteome homeostasis, or proteostasis, is essential to maintain cellular fitness and its disturbance is associated with a broad range of human health conditions and diseases. Cells are constantly challenged by various extrinsic and intrinsic insults, which perturb cellular proteostasis and provoke proteotoxic stress. To counter proteomic perturbations and preserve proteostasis, cells mobilize the proteotoxic stress response (PSR), an evolutionarily conserved transcriptional program mediated by heat shock factor 1 (HSF1). The HSF1-mediated PSR guards the proteome against misfolding and aggregation. In addition to proteotoxic stress, emerging studies reveal that this proteostatic mechanism also responds to cellular energy state. This regulation is mediated by the key cellular metabolic sensor AMP-activated protein kinase (AMPK). In this review, we present an overview of the maintenance of proteostasis by HSF1, the metabolic regulation of the PSR, particularly focusing on AMPK, and their implications in the two major age-related diseases-diabetes mellitus and neurodegenerative disorders.
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Affiliation(s)
- Kuo-Hui Su
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Chengkai Dai
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
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50
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Corpas R, Revilla S, Ursulet S, Castro-Freire M, Kaliman P, Petegnief V, Giménez-Llort L, Sarkis C, Pallàs M, Sanfeliu C. SIRT1 Overexpression in Mouse Hippocampus Induces Cognitive Enhancement Through Proteostatic and Neurotrophic Mechanisms. Mol Neurobiol 2016; 54:5604-5619. [PMID: 27614878 DOI: 10.1007/s12035-016-0087-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/26/2016] [Indexed: 01/08/2023]
Abstract
SIRT1 induces cell survival and has shown neuroprotection against amyloid and tau pathologies in Alzheimer's disease (AD). However, protective effects against memory loss or the enhancement of cognitive functions have not yet been proven. We aimed to investigate the benefits induced by SIRT1 overexpression in the hippocampus of the AD mouse model 3xTg-AD and in control non-transgenic mice. A lentiviral vector encoding mouse SIRT1 or GFP, selectively transducing neurons, was injected into the dorsal CA1 hippocampal area of 4-month-old mice. Six-month overexpression of SIRT1 fully preserved learning and memory in 10-month-old 3xTg-AD mice. Remarkably, SIRT1 also induced cognitive enhancement in healthy non-transgenic mice. Neuron cultures of 3xTg-AD mice, which show traits of AD-like pathology, and neuron cultures from non-transgenic mice were also transduced with lentiviral vectors to analyze beneficial SIRT1 mechanisms. We uncovered novel pathways of SIRT1 neuroprotection through enhancement of cell proteostatic mechanisms and activation of neurotrophic factors not previously reported such as GDNF, present in both AD-like and healthy neurons. Therefore, SIRT1 may increase neuron function and resilience against AD.
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Affiliation(s)
- Rubén Corpas
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain
| | - Susana Revilla
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain
| | | | - Marco Castro-Freire
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain
| | - Perla Kaliman
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain
| | - Valérie Petegnief
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain
| | - Lydia Giménez-Llort
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain
| | | | - Mercè Pallàs
- Facultat de Farmàcia, Institut de Neurociències, Universitat de Barcelona and CIBERNED, 08028, Barcelona, Spain
| | - Coral Sanfeliu
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain. .,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
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