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Gao Z, Qiu R, Dave DR, Chandravanshi P, Soares GP, Smith CS, Ortega JA, Palmer LC, Álvarez Z, Stupp SI. Supramolecular Copolymerization of Glycopeptide Amphiphiles and Amyloid Peptides Improves Neuron Survival. J Am Chem Soc 2025. [PMID: 40365999 DOI: 10.1021/jacs.5c00105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis are characterized by progressive neuronal loss and the accumulation of misfolded proteins including amyloid proteins. Current therapeutic options include the use of antibodies for these proteins, but novel chemical strategies need to be developed. The disaccharide trehalose has been widely reported to prevent misfolding and aggregation of proteins, and we therefore investigated the conjugation of this moiety to biocompatible peptide amphiphiles (TPAs) known to undergo supramolecular polymerization. Using X-ray scattering, circular dichroism, and infrared spectroscopy, we found that trehalose conjugation destabilized the internal β-sheet structures within the TPA supramolecular polymers as evidenced by a lower thermal transition. Thioflavin T fluorescence showed that these metastable TPA nanofibers suppressed A42 aggregation. Interestingly, we found that the suppression involved supramolecular copolymerization of TPA polymers with Aβ42, which effectively trapped the peptides within the filamentous structures. In vitro assays with human induced pluripotent stem cell-derived neurons demonstrated that these TPAs significantly improved neuron survival compared to other conditions. Our study highlights the potential of properly tuned supramolecular polymerizations of monomers to safely remove amyloidogenic proteins in neurodegeneration.
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Affiliation(s)
- Zijun Gao
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
| | - Ruomeng Qiu
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
| | - Dhwanit R Dave
- Center for Regenerative Nanomedicine Northwestern University 303 E. Superior Street, Chicago, Illinois 60611, United States
| | - Palash Chandravanshi
- Biomaterials for Neural Regeneration Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
- CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid 28029, Spain
| | - Gisele P Soares
- Department of Pathology and Experimental Therapeutics, Institute of Neurosciences, University of Barcelona L'Hospitalet de Llobregat, Barcelona 08907, Spain
- Neurodevelopmental Disorders Group, NeuroBell, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain
| | - Cara S Smith
- Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
- Center for Regenerative Nanomedicine Northwestern University 303 E. Superior Street, Chicago, Illinois 60611, United States
| | - J Alberto Ortega
- Department of Pathology and Experimental Therapeutics, Institute of Neurosciences, University of Barcelona L'Hospitalet de Llobregat, Barcelona 08907, Spain
- Neurodevelopmental Disorders Group, NeuroBell, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain
| | - Liam C Palmer
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
- Center for Regenerative Nanomedicine Northwestern University 303 E. Superior Street, Chicago, Illinois 60611, United States
| | - Zaida Álvarez
- Biomaterials for Neural Regeneration Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
- Center for Regenerative Nanomedicine Northwestern University 303 E. Superior Street, Chicago, Illinois 60611, United States
- Department of Medicine, Northwestern University, Chicago, Illinois 60611, United States
- CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid 28029, Spain
| | - Samuel I Stupp
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
- Biomaterials for Neural Regeneration Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
- Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
- Center for Regenerative Nanomedicine Northwestern University 303 E. Superior Street, Chicago, Illinois 60611, United States
- Department of Medicine, Northwestern University, Chicago, Illinois 60611, United States
- Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois 60208, United States
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de Carvalho Vilar MD, Coutinho KMD, de Lima Vale SH, Dourado Junior MET, de Medeiros GCBS, Piuvezam G, Brandao-Neto J, Leite-Lais L. Evidence-Based Nutritional Recommendations for Maintaining or Restoring Nutritional Status in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review. Nutrients 2025; 17:782. [PMID: 40077653 PMCID: PMC11901627 DOI: 10.3390/nu17050782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Background/Objectives: This study is a systematic review of guidelines that aims to synthesize evidence-based recommendations to support appropriate nutritional management for patients with amyotrophic lateral sclerosis (ALS). Methods: PubMed/MEDLINE, Embase, Scopus, SciELO, Web of Science, LILACS, ScienceDirect, and Google Scholar were searched for records published up to July 2024. Clinical practice guidelines addressing any aspect of nutritional intervention in ALS were included. No language or country of publication restrictions were applied. Data extraction was performed by two independent reviewers. The methodological quality of the reports was assessed using the AGREE II instrument. Discrepancies were resolved by consensus. Results: The findings and main recommendations were summarized narratively. A total of 837 records were identified, and 11 were included in this review. The overall AGREE II scores for the included studies ranged from 3 to 7. The summary of nutritional recommendations was organized into topics: (1) dysphagia, (2) nutritional assessment, (3) energy, (4) protein, (5) supplementation, and (6) percutaneous endoscopic gastrostomy (PEG). This review summarizes relevant and updated nutritional recommendations to maintain or restore the nutritional status of patients with ALS, contributing to their quality of life and survival time. Conclusions: These nutritional recommendations will help health professionals and caregivers to implement and standardize nutritional care according to evidence-based practice in ALS. PROSPERO registration number CRD42021233088.
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Affiliation(s)
- Mariana Dantas de Carvalho Vilar
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal 59012-300, Brazil; (M.D.d.C.V.); (S.H.d.L.V.); (G.P.); (J.B.-N.)
- Laboratory of Technological Innovation in Health (LAIS), Federal University of Rio Grande do Norte, Natal 59012-300, Brazil;
- Systematic Review and Meta-Analysis Laboratory-Lab-SYS/CNPq, Natal 59078-970, Brazil;
| | - Karla Monica Dantas Coutinho
- Laboratory of Technological Innovation in Health (LAIS), Federal University of Rio Grande do Norte, Natal 59012-300, Brazil;
| | - Sancha Helena de Lima Vale
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal 59012-300, Brazil; (M.D.d.C.V.); (S.H.d.L.V.); (G.P.); (J.B.-N.)
- Systematic Review and Meta-Analysis Laboratory-Lab-SYS/CNPq, Natal 59078-970, Brazil;
- Department of Nutrition, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | | | | | - Grasiela Piuvezam
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal 59012-300, Brazil; (M.D.d.C.V.); (S.H.d.L.V.); (G.P.); (J.B.-N.)
- Systematic Review and Meta-Analysis Laboratory-Lab-SYS/CNPq, Natal 59078-970, Brazil;
- Department of Public Health, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Jose Brandao-Neto
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal 59012-300, Brazil; (M.D.d.C.V.); (S.H.d.L.V.); (G.P.); (J.B.-N.)
| | - Lucia Leite-Lais
- Laboratory of Technological Innovation in Health (LAIS), Federal University of Rio Grande do Norte, Natal 59012-300, Brazil;
- Systematic Review and Meta-Analysis Laboratory-Lab-SYS/CNPq, Natal 59078-970, Brazil;
- Department of Nutrition, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
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Couturier N, Hörner SJ, Nürnberg E, Joazeiro C, Hafner M, Rudolf R. Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model. Front Cell Dev Biol 2024; 12:1429759. [PMID: 38966427 PMCID: PMC11222430 DOI: 10.3389/fcell.2024.1429759] [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: 05/08/2024] [Accepted: 06/03/2024] [Indexed: 07/06/2024] Open
Abstract
Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca2+ response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.
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Affiliation(s)
- Nathalie Couturier
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Sarah Janice Hörner
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Elina Nürnberg
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
| | - Claudio Joazeiro
- Center for Molecular Biology, Heidelberg University, Heidelberg, Germany
| | - Mathias Hafner
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Mannheim, Germany
- Institute of Medical Technology, Mannheim University of Applied Sciences and Heidelberg University, Mannheim, Germany
| | - Rüdiger Rudolf
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Mannheim, Germany
- Institute of Medical Technology, Mannheim University of Applied Sciences and Heidelberg University, Mannheim, Germany
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Zhong R, Rua MT, Wei-LaPierre L. Targeting mitochondrial Ca 2+ uptake for the treatment of amyotrophic lateral sclerosis. J Physiol 2024; 602:1519-1549. [PMID: 38010626 PMCID: PMC11032238 DOI: 10.1113/jp284143] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/31/2023] [Indexed: 11/29/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.
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Affiliation(s)
- Renjia Zhong
- Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, 32611
- Department of Emergency Medicine, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China, 110001
| | - Michael T. Rua
- Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, 32611
| | - Lan Wei-LaPierre
- Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, 32611
- Myology Institute, University of Florida, Gainesville, FL 32611
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Wang H, Zhao Y, Zhang D, Li J, Yang K, Yang J, Li B. Neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epilepsy in rats and its underlying mechanisms. Eur J Med Res 2024; 29:121. [PMID: 38355613 PMCID: PMC10865707 DOI: 10.1186/s40001-024-01694-x] [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: 12/18/2023] [Accepted: 01/24/2024] [Indexed: 02/16/2024] Open
Abstract
INTRODUCTION Epilepsy is a common neurological disorder that presents with challenging mechanisms and treatment strategies. This study investigated the neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epileptic rats and explored its potential mechanisms. METHODS Lithium chloride pilocarpine was used to induce an epileptic model in rats, and the effects of quinpirole on seizure symptoms and cognitive function were evaluated. The Racine scoring method, electroencephalography, and Morris water maze test were used to assess seizure severity and learning and memory functions in rats in the epileptic group. Additionally, immunohistochemistry and Western blot techniques were used to analyze the protein expression levels and morphological changes in glutamate receptor 2 (GluR2; GRIA2), BAX, and BCL2 in the hippocampi of rats in the epileptic group. RESULTS First, it was confirmed that the symptoms in rats in the epileptic group were consistent with features of epilepsy. Furthermore, these rats demonstrated decreased learning and memory function in the Morris water maze test. Additionally, gene and protein levels of GluR2 in the hippocampi of rats in the epileptic group were significantly reduced. Quinpirole treatment significantly delayed seizure onset and decreased the mortality rate after the induction of a seizure. Furthermore, electroencephalography showed a significant decrease in the frequency of the spike waves. In the Morris water maze test, rats from the quinpirole treatment group demonstrated a shorter latency period to reach the platform and an increased number of crossings through the target quadrant. Network pharmacology analysis revealed a close association between quinpirole and GluR2 as well as its involvement in the cAMP signaling pathway, cocaine addiction, and dopaminergic synapses. Furthermore, immunohistochemistry and Western blot analysis showed that quinpirole treatment resulted in a denser arrangement and a more regular morphology of the granule cells in the hippocampi of rats in the epileptic group. Additionally, quinpirole treatment decreased the protein expression of BAX and increased the protein expression of BCL2. CONCLUSION The current study demonstrated that quinpirole exerted neuroprotective effects in the epileptic rat model induced by lithium chloride pilocarpine. Additionally, it was found that the treatment not only alleviated the rats' seizure symptoms, but also improved their learning and memory abilities. This improvement was linked to the modulation of protein expression levels of GLUR2, BAX, and BCL2. These findings provided clues that would be important for further investigation of the therapeutic potential of quinpirole and its underlying mechanisms for epilepsy treatment.
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Affiliation(s)
- Hui Wang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Department of Pediatrics, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Yongheng Zhao
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Dongqing Zhang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jun Li
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Kun Yang
- Department of Pediatrics, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Junli Yang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
| | - Baomin Li
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
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Collyer E, Boyle BR, Gomez-Galvez Y, Iacovitti L, Blanco-Suarez E. Absence of chordin-like 1 aids motor recovery in a mouse model of stroke. Exp Neurol 2023; 370:114548. [PMID: 37769794 PMCID: PMC11905929 DOI: 10.1016/j.expneurol.2023.114548] [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: 07/05/2023] [Revised: 09/06/2023] [Accepted: 09/24/2023] [Indexed: 10/03/2023]
Abstract
Chordin-like 1 (Chrdl1) is an astrocyte-secreted protein that regulates synaptic maturation, and limits plasticity via GluA2-containing AMPA receptors (AMPARs). It was demonstrated that Chrdl1 expression is very heterogeneous throughout the brain, and it is enriched in astrocytes in cortical layers 2/3, with peak expression in the visual cortex at postnatal day 14. In response to ischemic stroke, Chrdl1 is upregulated during the acute and sub-acute phases in the peri-infarct region, potentially hindering recovery after stroke. Here, we used photothrombosis to model ischemic stroke in the motor cortex of adult male and female mice. In this study, we demonstrate that elimination of Chrdl1 in a global knock-out mouse reduces apoptotic cell death at early post-stroke stages and prevents ischemia-driven synaptic loss of AMPA receptors at later time points, all contributing to faster motor recovery. This suggests that synapse-regulating astrocyte-secreted proteins such as Chrdl1 have therapeutic potential to aid functional recovery after an ischemic injury.
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Affiliation(s)
- Eileen Collyer
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Bridget R Boyle
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Yolanda Gomez-Galvez
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lorraine Iacovitti
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Elena Blanco-Suarez
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
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Yong W, He D, Chen T, Rui Z, Wen Y, Wong KF, Sun L, Qi X, Guo J. Activation of N-Methyl-D-aspartate receptor contributed to the ultrasonic modulation of neurons in vitro. Biochem Biophys Res Commun 2023; 676:42-47. [PMID: 37481942 DOI: 10.1016/j.bbrc.2023.07.034] [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: 05/31/2023] [Accepted: 07/15/2023] [Indexed: 07/25/2023]
Abstract
Ultrasound stimulation is increasingly used to investigate brain function and treat brain diseases due to its high level of safety and precise spatiotemporal resolution. Therefore, it is crucial to understand the underlying mechanisms involved in ultrasound brain stimulation. In this study, we investigate the role of NMDA receptors in mediating the effects of ultrasound on primary hippocampal neurons in mice. Our results show that ultrasound alone can activate heterologous NMDA receptor subunits, including NR1A, NR2A, and NR2B, in 293T cells, as well as endogenous NMDA receptors in primary neurons. This activation leads to an influx of calcium and an increase in nuclear c-Fos expression in primary neurons that have not been pre-treated with an NMDA receptor inhibitor. In conclusion, our findings demonstrate that NMDA receptors contribute to neuronal activation by ultrasound stimulation in vitro, providing insight into the molecular mechanisms of ultrasound neuromodulation and a new mediator for the sonogenetics technique.
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Affiliation(s)
- Wu Yong
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, China; Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China
| | - Dongming He
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, China
| | - Taiheng Chen
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, China
| | - Zeng Rui
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, China
| | - Yinchuan Wen
- Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, China
| | - Kin Fung Wong
- Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China
| | - Lei Sun
- Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China
| | - Xiaofei Qi
- Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, China.
| | - Jinghui Guo
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, China; School of Medicine, The Chinese University of Hong Kong, Shenzhen, 518172, Guangdong, China.
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Tomiyama ALMR, Cartarozzi LP, de Oliveira Coser L, Chiarotto GB, Oliveira ALR. Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1 G93A mice. Front Cell Neurosci 2023; 17:1211486. [PMID: 37711512 PMCID: PMC10498468 DOI: 10.3389/fncel.2023.1211486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/07/2023] [Indexed: 09/16/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively affects motoneurons, causing muscle atrophy and evolving to death. Astrocytes inhibit the expression of MHC-I by neurons, contributing to a degenerative outcome. The present study verified the influence of interferon β (IFN β) treatment, a proinflammatory cytokine that upregulates MHC-I expression, in SOD1G93A transgenic mice. For that, 17 days old presymptomatic female mice were subjected to subcutaneous application of IFN β (250, 1,000, and 10,000 IU) every other day for 20 days. Rotarod motor test, clinical score, and body weight assessment were conducted every third day throughout the treatment period. No significant intergroup variations were observed in such parameters during the pre-symptomatic phase. All mice were then euthanized, and the spinal cords collected for comparative analysis of motoneuron survival, reactive gliosis, synapse coverage, microglia morphology classification, cytokine analysis by flow cytometry, and RT-qPCR quantification of gene transcripts. Additionally, mice underwent Rotarod motor assessment, weight monitoring, and neurological scoring. The results show that IFN β treatment led to an increase in the expression of MHC-I, which, even at the lowest dose (250 IU), resulted in a significant increase in neuronal survival in the ALS presymptomatic period which lasted until the onset of the disease. The treatment also influenced synaptic preservation by decreasing excitatory inputs and upregulating the expression of AMPA receptors by astrocytes. Microglial reactivity quantified by the integrated density of pixels did not decrease with treatment but showed a less activated morphology, coupled with polarization to an M1 profile. Disease progression upregulated gene transcripts for pro- and anti-inflammatory cytokines, and IFN β treatment significantly decreased mRNA expression for IL4. Overall, the present results demonstrate that a low dosage of IFN β shows therapeutic potential by increasing MHC-I expression, resulting in neuroprotection and immunomodulation.
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Affiliation(s)
| | | | | | | | - Alexandre L. R. Oliveira
- Department of Structural and Functional Biology, Institute of Biology—University of Campinas (UNICAMP), Campinas, Brazil
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Acosta-Galeana I, Hernández-Martínez R, Reyes-Cruz T, Chiquete E, Aceves-Buendia JDJ. RNA-binding proteins as a common ground for neurodegeneration and inflammation in amyotrophic lateral sclerosis and multiple sclerosis. Front Mol Neurosci 2023; 16:1193636. [PMID: 37475885 PMCID: PMC10355071 DOI: 10.3389/fnmol.2023.1193636] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/14/2023] [Indexed: 07/22/2023] Open
Abstract
The neurodegenerative and inflammatory illnesses of amyotrophic lateral sclerosis and multiple sclerosis were once thought to be completely distinct entities that did not share any remarkable features, but new research is beginning to reveal more information about their similarities and differences. Here, we review some of the pathophysiological features of both diseases and their experimental models: RNA-binding proteins, energy balance, protein transportation, and protein degradation at the molecular level. We make a thorough analysis on TDP-43 and hnRNP A1 dysfunction, as a possible common ground in both pathologies, establishing a potential link between neurodegeneration and pathological immunity. Furthermore, we highlight the putative variations that diverge from a common ground in an atemporal course that proposes three phases for all relevant molecular events.
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Affiliation(s)
| | | | - Tania Reyes-Cruz
- Laboratorio de Biología Molecular, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Mexico City, Mexico
| | - Erwin Chiquete
- Departamento de Neurología y Psiquiatría, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jose de Jesus Aceves-Buendia
- Departamento de Neurología y Psiquiatría, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Stoklund Dittlau K, Van Den Bosch L. Why should we care about astrocytes in a motor neuron disease? FRONTIERS IN MOLECULAR MEDICINE 2023; 3:1047540. [PMID: 39086676 PMCID: PMC11285655 DOI: 10.3389/fmmed.2023.1047540] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 01/13/2023] [Indexed: 08/02/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.
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Affiliation(s)
- Katarina Stoklund Dittlau
- KU Leuven—University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium
- VIB Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, Belgium
| | - Ludo Van Den Bosch
- KU Leuven—University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium
- VIB Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, Belgium
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11
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Fan Y, Huang H, Shao J, Huang W. MicroRNA-mediated regulation of reactive astrocytes in central nervous system diseases. Front Mol Neurosci 2023; 15:1061343. [PMID: 36710937 PMCID: PMC9877358 DOI: 10.3389/fnmol.2022.1061343] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/22/2022] [Indexed: 01/15/2023] Open
Abstract
Astrocytes (AST) are abundant glial cells in the human brain, accounting for approximately 20-50% percent of mammalian central nervous system (CNS) cells. They display essential functions necessary to sustain the physiological processes of the CNS, including maintaining neuronal structure, forming the blood-brain barrier, coordinating neuronal metabolism, maintaining the extracellular environment, regulating cerebral blood flow, stabilizing intercellular communication, participating in neurotransmitter synthesis, and defending against oxidative stress et al. During the pathological development of brain tumors, stroke, spinal cord injury (SCI), neurodegenerative diseases, and other neurological disorders, astrocytes undergo a series of highly heterogeneous changes, which are called reactive astrocytes, and mediate the corresponding pathophysiological process. However, the pathophysiological mechanisms of reactive astrocytes and their therapeutic relevance remain unclear. The microRNAs (miRNAs) are essential for cell differentiation, proliferation, and survival, which play a crucial role in the pathophysiological development of CNS diseases. In this review, we summarize the regulatory mechanism of miRNAs on reactive astrocytes in CNS diseases, which might provide a theoretical basis for the diagnosis and treatment of CNS diseases.
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12
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Provenzano F, Nyberg S, Giunti D, Torazza C, Parodi B, Bonifacino T, Usai C, Kerlero de Rosbo N, Milanese M, Uccelli A, Shaw PJ, Ferraiuolo L, Bonanno G. Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS. Cells 2022; 11:cells11233923. [PMID: 36497181 PMCID: PMC9741322 DOI: 10.3390/cells11233923] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes' neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell (MSC) administration in SOD1G93A ALS mice, but the mechanisms are still unclear. We postulated that the effects could be mediated by extracellular vesicles (EVs) secreted by MSCs. We investigated, by immunohistochemical, molecular, and in vitro functional analyses, the activity of MSC-derived EVs on the pathological phenotype and neurotoxicity of astrocytes isolated from the spinal cord of symptomatic SOD1G93A mice and human astrocytes (iAstrocytes) differentiated from inducible neural progenitor cells (iNPCs) of ALS patients. In vitro EV exposure rescued mouse and human ALS astrocytes' neurotoxicity towards MNs. EVs significantly dampened the pathological phenotype and neuroinflammation in SOD1G93A astrocytes. In iAstrocytes, exposure to EVs increased the antioxidant factor Nrf2 and reduced reactive oxygen species. We previously found nine miRNAs upregulated in MSC-derived EVs. Here, the transfection of SOD1G93A astrocytes with single miRNA mimics reduced astrocytes' activation and the expression of neuroinflammatory factors. Moreover, miR-466q and miR-467f mimics downregulate Mapk11, while miR-466m-5p and miR-466i-3p mimics promote the nuclear translocation of Nrf2. In iAstrocytes, transfection with miR-29b-3p mimic upregulated NQO1 antioxidant activity and reduced neurotoxicity towards MNs. MSC-derived EVs modulate astrocytes' reactive phenotype and neurotoxicity through anti-inflammatory and antioxidant-shuttled miRNAs, thus representing a therapeutic strategy in ALS.
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Affiliation(s)
- Francesca Provenzano
- Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, 16148 Genova, Italy
| | - Sophie Nyberg
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK
| | - Debora Giunti
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Paolo Daneo, 316132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy
| | - Carola Torazza
- Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, 16148 Genova, Italy
| | - Benedetta Parodi
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Paolo Daneo, 316132 Genoa, Italy
| | - Tiziana Bonifacino
- Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, 16148 Genova, Italy
- Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 56122 Pisa, Italy
| | - Cesare Usai
- Institute of Biophysics, National Research Council (CNR), Via De Marini 6, 16149 Genoa, Italy
| | - Nicole Kerlero de Rosbo
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy
- TomaLab, Institute of Nanotechnology, National Research Council (CNR), Piazzale Aldo Moro 5, 0018 Rome, Italy
| | - Marco Milanese
- Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, 16148 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy
- Correspondence: (M.M.); (L.F.); Tel.: +39-01-0335-2046 (M.M.); +44-(0)114-222-2257 (L.F.)
| | - Antonio Uccelli
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Paolo Daneo, 316132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy
| | - Pamela J. Shaw
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK
| | - Laura Ferraiuolo
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK
- Correspondence: (M.M.); (L.F.); Tel.: +39-01-0335-2046 (M.M.); +44-(0)114-222-2257 (L.F.)
| | - Giambattista Bonanno
- Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, 16148 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy
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13
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Vilar MDDC, Coutinho KMD, Vale SHDL, Medeiros GCBS, Piuvezam G, Leite-Lais L, Brandao-Neto J. Nutritional therapy in amyotrophic lateral sclerosis: protocol for a systematic review and meta-analysis. BMJ Open 2022; 12:e064086. [PMID: 36008057 PMCID: PMC9422859 DOI: 10.1136/bmjopen-2022-064086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterised by the degeneration of motor neurons. Nutritional interventions in ALS are essential and must be based on scientific evidence to provide quality of healthcare, improve the quality of life and increase survival time. Therefore, this protocol of systematic reviews and meta-analyses aims to present a synthesis of evidence-based recommendations to support adequate nutrition therapy for patients with ALS. METHODS AND ANALYSIS The search will be performed using the following databases: PubMed, Excerpta Medica Database (Embase), Scopus, SciELO, Web of Science, LILACS, Cochrane Central Register of Controlled Trials (CENTRAL), ScienceDirect, ProQuest and Google Scholar. We will include clinical practice guidelines, treatment protocols, systematic reviews and clinical trials according to the three research questions to be answered related to nutrition therapy and interventions in patients with ALS. This protocol will be developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols. To evaluate the methodological quality of the studies, Appraisal of Guidelines, Research and Evaluation II, Cochrane Risk of Bias 2.0 and Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tools will be used. In addition, the Grading of Recommendations Assessment, Development and Evaluation will be used to assess the quality of evidence and the strength of the recommendations. The findings will be summarised and presented descriptively according to the Cochrane Collaboration Handbook and the standard statistical meta-analysis techniques. ETHICS AND DISSEMINATION Ethical approval and human consent are not required because this is a protocol for systematic review and only secondary data will be used. Findings will be published in a peer-reviewed journal and presented at conferences. In case of any changes in this protocol, amendments will be updated in International Prospective Register of Systematic Reviews (PROSPERO) and the modifications will be explained in the final report of this review. PROSPERO REGISTRATION NUMBER CRD42021233088.
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Affiliation(s)
- Mariana Dantas de Carvalho Vilar
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
- Laboratory of Technological Innovation in Health (LAIS), Federal University of Rio Grande do Norte, Natal, Brazil
| | - Karla Monica Dantas Coutinho
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
- Laboratory of Technological Innovation in Health (LAIS), Federal University of Rio Grande do Norte, Natal, Brazil
| | - Sancha Helena de Lima Vale
- Laboratory of Technological Innovation in Health (LAIS), Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Nutrition, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Gidyenne Christine Bandeira Silva Medeiros
- Department of Nutrition, Federal University of Rio Grande do Norte, Natal, Brazil
- Systematic Review and Meta-Analysis Laboratory (LabSys), Federal University of Rio Grande do Norte, Natal, Brazil
| | - Grasiela Piuvezam
- Systematic Review and Meta-Analysis Laboratory (LabSys), Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Public Health, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Lucia Leite-Lais
- Laboratory of Technological Innovation in Health (LAIS), Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Nutrition, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Jose Brandao-Neto
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Internal Medicine, Federal University of Rio Grande do Norte, Natal, Brazil
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14
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Huang J, Li C, Shang H. Astrocytes in Neurodegeneration: Inspiration From Genetics. Front Neurosci 2022; 16:882316. [PMID: 35812232 PMCID: PMC9268899 DOI: 10.3389/fnins.2022.882316] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/06/2022] [Indexed: 12/19/2022] Open
Abstract
Despite the discovery of numerous molecules and pathologies, the pathophysiology of various neurodegenerative diseases remains unknown. Genetics participates in the pathogenesis of neurodegeneration. Neural dysfunction, which is thought to be a cell-autonomous mechanism, is insufficient to explain the development of neurodegenerative disease, implying that other cells surrounding or related to neurons, such as glial cells, are involved in the pathogenesis. As the primary component of glial cells, astrocytes play a variety of roles in the maintenance of physiological functions in neurons and other glial cells. The pathophysiology of neurodegeneration is also influenced by reactive astrogliosis in response to central nervous system (CNS) injuries. Furthermore, those risk-gene variants identified in neurodegenerations are involved in astrocyte activation and senescence. In this review, we summarized the relationships between gene variants and astrocytes in four neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), and provided insights into the implications of astrocytes in the neurodegenerations.
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15
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Satarker S, Bojja SL, Gurram PC, Mudgal J, Arora D, Nampoothiri M. Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders. Cells 2022; 11:cells11071139. [PMID: 35406702 PMCID: PMC8997779 DOI: 10.3390/cells11071139] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/12/2022] [Accepted: 03/13/2022] [Indexed: 12/11/2022] Open
Abstract
Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value.
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Affiliation(s)
- Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India; (S.S.); (S.L.B.); (P.C.G.); (J.M.)
| | - Sree Lalitha Bojja
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India; (S.S.); (S.L.B.); (P.C.G.); (J.M.)
| | - Prasada Chowdari Gurram
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India; (S.S.); (S.L.B.); (P.C.G.); (J.M.)
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India; (S.S.); (S.L.B.); (P.C.G.); (J.M.)
| | - Devinder Arora
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India; (S.S.); (S.L.B.); (P.C.G.); (J.M.)
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, QLD 4222, Australia;
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India; (S.S.); (S.L.B.); (P.C.G.); (J.M.)
- Correspondence:
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16
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Peggion C, Scalcon V, Massimino ML, Nies K, Lopreiato R, Rigobello MP, Bertoli A. SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells. Antioxidants (Basel) 2022; 11:614. [PMID: 35453299 PMCID: PMC9032988 DOI: 10.3390/antiox11040614] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 12/04/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. While the exact causes of ALS are still unclear, the discovery that familial cases of ALS are related to mutations in the Cu/Zn superoxide dismutase (SOD1), a key antioxidant enzyme protecting cells from the deleterious effects of superoxide radicals, suggested that alterations in SOD1 functionality and/or aberrant SOD1 aggregation strongly contribute to ALS pathogenesis. A new scenario was opened in which, thanks to the generation of SOD1 related models, different mechanisms crucial for ALS progression were identified. These include excitotoxicity, oxidative stress, mitochondrial dysfunctions, and non-cell autonomous toxicity, also implicating altered Ca2+ metabolism. While most of the literature considers motor neurons as primary target of SOD1-mediated effects, here we mainly discuss the effects of SOD1 mutations in non-neuronal cells, such as glial and skeletal muscle cells, in ALS. Attention is given to the altered redox balance and Ca2+ homeostasis, two processes that are strictly related with each other. We also provide original data obtained in primary myocytes derived from hSOD1(G93A) transgenic mice, showing perturbed expression of Ca2+ transporters that may be responsible for altered mitochondrial Ca2+ fluxes. ALS-related SOD1 mutants are also responsible for early alterations of fundamental biological processes in skeletal myocytes that may impinge on skeletal muscle functions and the cross-talk between muscle cells and motor neurons during disease progression.
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Affiliation(s)
- Caterina Peggion
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; (C.P.); (V.S.); (K.N.); (R.L.)
| | - Valeria Scalcon
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; (C.P.); (V.S.); (K.N.); (R.L.)
| | | | - Kelly Nies
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; (C.P.); (V.S.); (K.N.); (R.L.)
- Department of Radiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Raffaele Lopreiato
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; (C.P.); (V.S.); (K.N.); (R.L.)
| | - Maria Pia Rigobello
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; (C.P.); (V.S.); (K.N.); (R.L.)
| | - Alessandro Bertoli
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; (C.P.); (V.S.); (K.N.); (R.L.)
- CNR—Neuroscience Institute, 35131 Padova, Italy;
- Padova Neuroscience Center, University of Padova, 35131 Padova, Italy
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17
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Soubannier V, Chaineau M, Gursu L, Haghi G, Franco Flores AK, Rouleau G, Durcan TM, Stifani S. Rapid Generation of Ventral Spinal Cord-like Astrocytes from Human iPSCs for Modeling Non-Cell Autonomous Mechanisms of Lower Motor Neuron Disease. Cells 2022; 11:cells11030399. [PMID: 35159209 PMCID: PMC8834281 DOI: 10.3390/cells11030399] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/16/2022] [Accepted: 01/21/2022] [Indexed: 12/26/2022] Open
Abstract
Astrocytes play important roles in the function and survival of neuronal cells. Dysfunctions of astrocytes are associated with numerous disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Human-induced pluripotent stem cell (iPSC)-based approaches are becoming increasingly important for the study of the mechanisms underlying the involvement of astrocytes in non-cell autonomous processes of motor neuron degeneration in ALS. These studies must account for the molecular and functional diversity among astrocytes in different regions of the brain and spinal cord. It is essential that the most pathologically relevant astrocyte preparations are used when investigating non-cell autonomous mechanisms of either upper or lower motor neuron degeneration in ALS. Here, we describe the efficient and streamlined generation of human iPSC-derived astrocytes with molecular and biological properties similar to physiological astrocytes in the ventral spinal cord. These induced astrocytes exhibit spontaneous and ATP-induced calcium transients, and lack signs of overt activation. Human iPSC-derived astrocytes with ventral spinal cord features offer advantages over more generic astrocyte preparations for the study of both ventral spinal cord astrocyte biology and the involvement of astrocytes in mechanisms of lower motor neuron degeneration in ALS.
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Affiliation(s)
- Vincent Soubannier
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (V.S.); (G.R.); (T.M.D.)
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (M.C.); (L.G.); (G.H.); (A.K.F.F.)
| | - Mathilde Chaineau
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (M.C.); (L.G.); (G.H.); (A.K.F.F.)
| | - Lale Gursu
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (M.C.); (L.G.); (G.H.); (A.K.F.F.)
| | - Ghazal Haghi
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (M.C.); (L.G.); (G.H.); (A.K.F.F.)
| | - Anna Kristyna Franco Flores
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (M.C.); (L.G.); (G.H.); (A.K.F.F.)
| | - Guy Rouleau
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (V.S.); (G.R.); (T.M.D.)
| | - Thomas M. Durcan
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (V.S.); (G.R.); (T.M.D.)
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (M.C.); (L.G.); (G.H.); (A.K.F.F.)
| | - Stefano Stifani
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada; (V.S.); (G.R.); (T.M.D.)
- Correspondence:
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18
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Craig CF, Filippone RT, Stavely R, Bornstein JC, Apostolopoulos V, Nurgali K. Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease. J Neuroinflammation 2022; 19:4. [PMID: 34983592 PMCID: PMC8729103 DOI: 10.1186/s12974-021-02354-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/14/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) suffer from depression at higher rates than the general population. An etiological trigger of depressive symptoms is theorised to be inflammation within the central nervous system. It is believed that heightened intestinal inflammation and dysfunction of the enteric nervous system (ENS) contribute to impaired intestinal permeability, which facilitates the translocation of intestinal enterotoxins into the blood circulation. Consequently, these may compromise the immunological and physiological functioning of distant non-intestinal tissues such as the brain. In vivo models of colitis provide evidence of increased blood–brain barrier permeability and enhanced central nervous system (CNS) immune activity triggered by intestinal enterotoxins and blood-borne inflammatory mediators. Understanding the immunological, physiological, and structural changes associated with IBD and neuroinflammation may aid in the development of more tailored and suitable pharmaceutical treatment for IBD-associated depression.
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Affiliation(s)
- Colin F Craig
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhiannon T Filippone
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhian Stavely
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Joel C Bornstein
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Australia
| | - Vasso Apostolopoulos
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Immunology Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Kulmira Nurgali
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia. .,Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia. .,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia. .,Institute for Health and Sport, Victoria University, Level 4 Research Labs, Western Centre for Health Research and Education, Sunshine Hospital, 176 Furlong Road, St Albans, VIC, 3021, Australia.
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19
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Rochat C, Bernard-Marissal N, Källstig E, Pradervand S, Perrin FE, Aebischer P, Raoul C, Schneider BL. Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis. Glia 2022; 70:842-857. [PMID: 34978340 PMCID: PMC9303637 DOI: 10.1002/glia.24140] [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: 09/23/2021] [Revised: 12/19/2021] [Accepted: 12/22/2021] [Indexed: 11/22/2022]
Abstract
In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell‐autonomous and noncell‐autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV‐gfaABC1D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast‐fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast‐twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast‐fatigable motor units and thereby improves neuromuscular function in ALS mice.
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Affiliation(s)
- Cylia Rochat
- Ecole Polytechnique Fédérale de Lausanne (EPFL), Brain Mind Institute, Lausanne
| | - Nathalie Bernard-Marissal
- Ecole Polytechnique Fédérale de Lausanne (EPFL), Brain Mind Institute, Lausanne.,INSERM, MMG, Aix-Marseille University, Marseille, France
| | - Emma Källstig
- Ecole Polytechnique Fédérale de Lausanne (EPFL), Brain Mind Institute, Lausanne.,Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne (EPFL), Geneva
| | - Sylvain Pradervand
- Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland
| | | | - Patrick Aebischer
- Ecole Polytechnique Fédérale de Lausanne (EPFL), Brain Mind Institute, Lausanne
| | - Cédric Raoul
- INM, Université Montpellier, INSERM, Montpellier, France
| | - Bernard L Schneider
- Ecole Polytechnique Fédérale de Lausanne (EPFL), Brain Mind Institute, Lausanne.,Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne (EPFL), Geneva
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20
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Senolytics: A Novel Strategy for Neuroprotection in ALS? Int J Mol Sci 2021; 22:ijms222112078. [PMID: 34769512 PMCID: PMC8584291 DOI: 10.3390/ijms222112078] [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: 09/20/2021] [Revised: 10/30/2021] [Accepted: 11/04/2021] [Indexed: 12/14/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.
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21
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Stifani S. Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells. Front Cell Neurosci 2021; 15:707861. [PMID: 34602979 PMCID: PMC8485040 DOI: 10.3389/fncel.2021.707861] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/24/2021] [Indexed: 12/25/2022] Open
Abstract
Astrocytes are a large group of glial cells that perform a variety of physiological functions in the nervous system. They provide trophic, as well as structural, support to neuronal cells. Astrocytes are also involved in neuroinflammatory processes contributing to neuronal dysfunction and death. Growing evidence suggests important roles for astrocytes in non-cell autonomous mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Understanding these mechanisms necessitates the combined use of animal and human cell-based experimental model systems, at least in part because human astrocytes display a number of unique features that cannot be recapitulated in animal models. Human induced pluripotent stem cell (hiPSC)-based approaches provide the opportunity to generate disease-relevant human astrocytes to investigate the roles of these cells in ALS. These approaches are facing the growing recognition that there are heterogenous populations of astrocytes in the nervous system which are not functionally equivalent. This review will discuss the importance of taking astrocyte heterogeneity into consideration when designing hiPSC-based strategies aimed at generating the most informative preparations to study the contribution of astrocytes to ALS pathophysiology.
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Affiliation(s)
- Stefano Stifani
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
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22
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All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration. Cells 2021; 10:cells10092438. [PMID: 34572087 PMCID: PMC8468417 DOI: 10.3390/cells10092438] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/12/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.
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23
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Bai Y, Su X, Piao L, Jin Z, Jin R. Involvement of Astrocytes and microRNA Dysregulation in Neurodegenerative Diseases: From Pathogenesis to Therapeutic Potential. Front Mol Neurosci 2021; 14:556215. [PMID: 33815055 PMCID: PMC8010124 DOI: 10.3389/fnmol.2021.556215] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 02/23/2021] [Indexed: 12/11/2022] Open
Abstract
Astrocytes are the most widely distributed and abundant glial cells in the central nervous system (CNS). Neurodegenerative diseases (NDDs) are a class of diseases with a slow onset, progressive progression, and poor prognosis. Common clinical NDDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Although these diseases have different etiologies, they are all associated with neuronal loss and pathological dysfunction. Accumulating evidence indicates that neurotransmitters, neurotrophic factors, and toxic metabolites that are produced and released by activated astrocytes affect and regulate the function of neurons at the receptor, ion channel, antigen transfer, and gene transcription levels in the pathogenesis of NDDs. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a wide range of biological roles by regulating the transcription and post-transcriptional translation of target mRNAs to induce target gene expression and silencing. Recent studies have shown that miRNAs participate in the pathogenesis of NDDs by regulating astrocyte function through different mechanisms and may be potential targets for the treatment of NDDs. Here, we review studies of the role of astrocytes in the pathogenesis of NDDs and discuss possible mechanisms of miRNAs in the regulation of astrocyte function, suggesting that miRNAs may be targeted as a novel approach for the treatment of NDDs.
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Affiliation(s)
- Yang Bai
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Xing Su
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, China
| | - Lianhua Piao
- College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Zheng Jin
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Rihua Jin
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
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24
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Han F, Ebrahimi-Barough S, Abolghasemi R, Ai J, Liu Y. Cell-Based Therapy for Spinal Muscular Atrophy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1266:117-125. [PMID: 33105498 DOI: 10.1007/978-981-15-4370-8_8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease characterized by the degeneration of lower motor neurons in the spinal cord, leading to progressive paralysis and early death in the severe cases. SMA is primarily caused by the mutations in the gene of SMN (survival motor neuron). More research has focused on the development of SMN-targeted replacement therapy for SMA. The first US Food and Drug Administration (FDA)-approved modified antisense oligonucleotide (nusinersen) to treat SMA is to reverse intronic splicing silencer of SMN to produce fully functional SMN2. Recently, stem cell transplantation has shown the potential to repair the injured tissue and differentiate into neurons to rescue the phenotypes of SMA in animal models. In this chapter, we first review the clinical, genetic, and pathogenic mechanisms of SMA. Then, we discuss current pharmacological treatments and point out the therapeutic efficacy of stem cell transplantation and future directions and priorities for SMA.
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Affiliation(s)
- Fabin Han
- The Institute for Translational Medicine, Shandong University/Affiliated Second Hospital, Jinan, Shandong, China. .,The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China.
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reyhaneh Abolghasemi
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yanming Liu
- The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
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25
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Trujillo-Estrada L, Gomez-Arboledas A, Forner S, Martini AC, Gutierrez A, Baglietto-Vargas D, LaFerla FM. Astrocytes: From the Physiology to the Disease. Curr Alzheimer Res 2020; 16:675-698. [PMID: 31470787 DOI: 10.2174/1567205016666190830110152] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/12/2019] [Accepted: 05/17/2019] [Indexed: 12/14/2022]
Abstract
Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In the present review, we highlight the physiological role of astrocytes in the CNS, including their communication with other cells in the brain. Furthermore, we discuss exciting findings and novel experimental approaches that elucidate the role of astrocytes in multiple neurological disorders.
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Affiliation(s)
- Laura Trujillo-Estrada
- Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA 92697-4545, United States
| | - Angela Gomez-Arboledas
- Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain.,Instituto de Investigación Biomédica de Malaga-IBIMA, Malaga, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Stefânia Forner
- Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA 92697-4545, United States
| | - Alessandra Cadete Martini
- Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA 92697-4545, United States
| | - Antonia Gutierrez
- Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain.,Instituto de Investigación Biomédica de Malaga-IBIMA, Malaga, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - David Baglietto-Vargas
- Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA 92697-4545, United States.,Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, United States
| | - Frank M LaFerla
- Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA 92697-4545, United States.,Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, United States
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26
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Le Gall L, Anakor E, Connolly O, Vijayakumar UG, Duddy WJ, Duguez S. Molecular and Cellular Mechanisms Affected in ALS. J Pers Med 2020; 10:E101. [PMID: 32854276 PMCID: PMC7564998 DOI: 10.3390/jpm10030101] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/17/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.
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Affiliation(s)
- Laura Le Gall
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
- NIHR Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UK
| | - Ekene Anakor
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - Owen Connolly
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - Udaya Geetha Vijayakumar
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - William J. Duddy
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - Stephanie Duguez
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
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27
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Clark CM, Clark RM, Hoyle JA, Dickson TC. Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis. J Neurochem 2020; 156:273-289. [PMID: 32654149 DOI: 10.1111/jnc.15125] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/16/2020] [Accepted: 06/24/2020] [Indexed: 12/13/2022]
Abstract
Neuropeptide Y (NPY) is an endogenous peptide of the central and enteric nervous systems which has gained significant interest as a potential neuroprotective agent for treatment of neurodegenerative disease. Amyotrophic lateral sclerosis (ALS) is an aggressive and fatal neurodegenerative disease characterized by motor deficits and motor neuron loss. In ALS, recent evidence from ALS patients and animal models has indicated that NPY may have a role in the disease pathogenesis. Increased NPY levels were found to correlate with disease progression in ALS patients. Similarly, NPY expression is increased in the motor cortex of ALS mice by end stages of the disease. Although the functional consequence of increased NPY levels in ALS is currently unknown, NPY has been shown to exert a diverse range of neuroprotective roles in other neurodegenerative diseases; through modulation of potassium channel activity, increased production of neurotrophins, inhibition of endoplasmic reticulum stress and autophagy, reduction of excitotoxicity, oxidative stress, neuroinflammation and hyperexcitability. Several of these mechanisms and signalling pathways are heavily implicated in the pathogenesis of ALS. Therefore, in this review, we discuss possible effects of NPY and NPY-receptor signalling in the ALS disease context, as determining NPY's contribution to, or impact on, ALS disease mechanisms will be essential for future studies investigating the NPY system as a therapeutic strategy in this devastating disease.
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Affiliation(s)
- Courtney M Clark
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Rosemary M Clark
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Joshua A Hoyle
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Tracey C Dickson
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
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28
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Liu L, Killoy KM, Vargas MR, Yamamoto Y, Pehar M. Effects of RAGE inhibition on the progression of the disease in hSOD1 G93A ALS mice. Pharmacol Res Perspect 2020; 8:e00636. [PMID: 32776498 PMCID: PMC7415959 DOI: 10.1002/prp2.636] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023] Open
Abstract
Astrocytes play a key role in the progression of amyotrophic lateral sclerosis (ALS) by actively inducing the degeneration of motor neurons. Motor neurons isolated from receptor for advanced glycation end products (RAGE)-knockout mice are resistant to the neurotoxic signal derived from ALS-astrocytes. Here, we confirmed that in a co-culture model, the neuronal death induced by astrocytes over-expressing the ALS-linked mutant hSOD1G93A is prevented by the addition of the RAGE inhibitors FPS-ZM1 or RAP. These inhibitors also prevented the motor neuron death induced by spinal cord extracts from symptomatic hSOD1G93A mice. To evaluate the relevance of this neurotoxic mechanism in ALS pathology, we assessed the therapeutic potential of FPS-ZM1 in hSOD1G93A mice. FPS-ZM1 treatment significantly improved hind-limb grip strength in hSOD1G93A mice during the progression of the disease, reduced the expression of atrophy markers in the gastrocnemius muscle, improved the survival of large motor neurons, and reduced gliosis in the ventral horn of the spinal cord. However, we did not observe a statistically significant effect of the drug in symptoms onset nor in the survival of hSOD1G93A mice. Maintenance of hind-limb grip strength was also observed in hSOD1G93A mice with RAGE haploinsufficiency [hSOD1G93A ;RAGE(+/-)], further supporting the beneficial effect of RAGE inhibition on muscle function. However, no benefits were observed after complete RAGE ablation. Moreover, genetic RAGE ablation significantly shortened the median survival of hSOD1G93A mice. These results indicate that the advance of new therapies targeting RAGE in ALS demands a better understanding of its physiological role in a cell type/tissue-specific context.
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Affiliation(s)
- Liping Liu
- Biomedical Sciences Training ProgramDepartment of Pharmacology and Experimental TherapeuticsMedical University of South CarolinaCharlestonSCUSA
| | - Kelby M. Killoy
- Biomedical Sciences Training ProgramDepartment of Pharmacology and Experimental TherapeuticsMedical University of South CarolinaCharlestonSCUSA
| | | | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular BiologyKanazawa University Graduate School of Medical SciencesKanazawaJapan
| | - Mariana Pehar
- Division of Geriatrics and GerontologyDepartment of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- Geriatric Research Education Clinical CenterVeterans Affairs Medical CenterMadisonWIUSA
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29
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Studying ALS: Current Approaches, Effect on Potential Treatment Strategy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1241:195-217. [PMID: 32383122 DOI: 10.1007/978-3-030-41283-8_11] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, characterized by inevitable progressive paralysis. To date, only two disease modifying therapeutic options are available for the patients with ALS, although they show very modest effect on disease course. The main reason of failure in the field of pharmacological correction of ALS is inability to untangle complex relationships taking place during ALS initiation and progression. Traditional methods of research, based on morphology or transgenic animal models studying provided lots of information about ALS throughout the years. However, translation of these results to humans was unsuccessful due to incomplete recapitulation of molecular pathology and overall inadequacy of the models used in the research.In this review we summarize current knowledge regarding ALS molecular pathology with depiction of novel methods applied recently for the studies. Furthermore we describe present and potential treatment strategies that are based on the recent findings in ALS disease mechanisms.
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30
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Gunes ZI, Kan VWY, Ye X, Liebscher S. Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology. Front Neurosci 2020; 14:573. [PMID: 32625051 PMCID: PMC7311855 DOI: 10.3389/fnins.2020.00573] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a much-improved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell type-specific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area- and disease stage- specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.
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Affiliation(s)
- Zeynep I Gunes
- Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig Maximilians University Munich, Munich, Germany.,Graduate School of Systemic Neurosciences, Ludwig Maximilians University Munich, Munich, Germany.,Biomedical Center, Ludwig Maximilians University Munich, Munich, Germany
| | - Vanessa W Y Kan
- Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig Maximilians University Munich, Munich, Germany.,Graduate School of Systemic Neurosciences, Ludwig Maximilians University Munich, Munich, Germany.,Biomedical Center, Ludwig Maximilians University Munich, Munich, Germany
| | - XiaoQian Ye
- Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig Maximilians University Munich, Munich, Germany.,Biomedical Center, Ludwig Maximilians University Munich, Munich, Germany
| | - Sabine Liebscher
- Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig Maximilians University Munich, Munich, Germany.,Biomedical Center, Ludwig Maximilians University Munich, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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31
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Gleichman AJ, Carmichael ST. Glia in neurodegeneration: Drivers of disease or along for the ride? Neurobiol Dis 2020; 142:104957. [PMID: 32512150 DOI: 10.1016/j.nbd.2020.104957] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 05/13/2020] [Accepted: 06/03/2020] [Indexed: 02/08/2023] Open
Abstract
While much of the research on neurodegenerative diseases has focused on neurons, non-neuronal cells are also affected. The extent to which glia and other non-neuronal cells are causally involved in disease pathogenesis versus more passively responding to disease is an area of active research. This is complicated by the fact that there is rarely one known cause of neurodegenerative diseases; rather, these disorders likely involve feedback loops that perpetuate dysfunction. Here, we will review genetic as well as experimental evidence that suggest that non-neuronal cells are at least partially driving disease pathogenesis in numerous neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and Parkinson's disease.
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Affiliation(s)
- Amy J Gleichman
- Department of Neurology, David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA 90095, United States.
| | - S Thomas Carmichael
- Department of Neurology, David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA 90095, United States
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32
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Armada-Moreira A, Gomes JI, Pina CC, Savchak OK, Gonçalves-Ribeiro J, Rei N, Pinto S, Morais TP, Martins RS, Ribeiro FF, Sebastião AM, Crunelli V, Vaz SH. Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases. Front Cell Neurosci 2020; 14:90. [PMID: 32390802 PMCID: PMC7194075 DOI: 10.3389/fncel.2020.00090] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/26/2020] [Indexed: 12/13/2022] Open
Abstract
Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.
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Affiliation(s)
- Adam Armada-Moreira
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark
| | - Joana I. Gomes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Carolina Campos Pina
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Oksana K. Savchak
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Joana Gonçalves-Ribeiro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Nádia Rei
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Sara Pinto
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Tatiana P. Morais
- Neuroscience Division, School of Bioscience, Cardiff University, Cardiff, United Kingdom
| | - Robertta Silva Martins
- Laboratório de Neurofarmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, Brazil
| | - Filipa F. Ribeiro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Ana M. Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Vincenzo Crunelli
- Neuroscience Division, School of Bioscience, Cardiff University, Cardiff, United Kingdom
- Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
| | - Sandra H. Vaz
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
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33
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Paudel YN, Angelopoulou E, Piperi C, Othman I, Shaikh MF. Implication of HMGB1 signaling pathways in Amyotrophic lateral sclerosis (ALS): From molecular mechanisms to pre-clinical results. Pharmacol Res 2020; 156:104792. [PMID: 32278047 DOI: 10.1016/j.phrs.2020.104792] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 02/14/2020] [Accepted: 04/01/2020] [Indexed: 02/06/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressing neurodegenerative disorder with no effective disease-modifying treatment up to date. The underlying molecular mechanisms of ALS are not yet completely understood. However, the critical role of the innate immune system and neuroinflammation in ALS pathogenesis has gained increased attention. High mobility group box 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, acting as a pro-inflammatory cytokine mainly through activation of its principal receptors, the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) which are crucial components of the innate immune system. HMGB1 is an endogenous ligand for both RAGE and TLR4 that mediate its biological effects. Herein, on the ground of pre-clinical findings we unravel the underlying mechanisms behind the plausible contribution of HMGB1 and its receptors (RAGE and TLR4) in the ALS pathogenesis. Furthermore, we provide an account of the therapeutic outcomes associated with inhibition/blocking of HMGB1 receptor signalling in preventing motor neuron's death and delaying disease progression in ALS experimental models. There is strong evidence that HMGB1, RAGE and TLR4 signaling axes might present potential targets against ALS, opening a novel headway in ALS research that could plausibly bridge the current treatment gap.
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Affiliation(s)
- Yam Nath Paudel
- Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.
| | - Efthalia Angelopoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| | - Iekhsan Othman
- Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | - Mohd Farooq Shaikh
- Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.
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34
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Belov Kirdajova D, Kriska J, Tureckova J, Anderova M. Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells. Front Cell Neurosci 2020; 14:51. [PMID: 32265656 PMCID: PMC7098326 DOI: 10.3389/fncel.2020.00051] [Citation(s) in RCA: 232] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/21/2020] [Indexed: 12/21/2022] Open
Abstract
A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is a prominent cause of death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose and oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion and ionic imbalance, followed by cell membrane depolarization, calcium (Ca2+) overload, and extracellular accumulation of excitatory amino acid glutamate. If tight physiological regulation fails to clear the surplus of this neurotransmitter, subsequent prolonged activation of glutamate receptors forms a vicious circle between elevated concentrations of intracellular Ca2+ ions and aberrant glutamate release, aggravating the effect of this ischemic pathway. The activation of downstream Ca2+-dependent enzymes has a catastrophic impact on nervous tissue leading to cell death, accompanied by the formation of free radicals, edema, and inflammation. After decades of “neuron-centric” approaches, recent research has also finally shed some light on the role of glial cells in neurological diseases. It is becoming more and more evident that neurons and glia depend on each other. Neuronal cells, astrocytes, microglia, NG2 glia, and oligodendrocytes all have their roles in what is known as glutamate excitotoxicity. However, who is the main contributor to the ischemic pathway, and who is the unsuspecting victim? In this review article, we summarize the so-far-revealed roles of cells in the central nervous system, with particular attention to glial cells in ischemia-induced glutamate excitotoxicity, its origins, and consequences.
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Affiliation(s)
- Denisa Belov Kirdajova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia.,Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Jan Kriska
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia.,Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Jana Tureckova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia
| | - Miroslava Anderova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia.,Second Faculty of Medicine, Charles University, Prague, Czechia
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35
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Bursch F, Kalmbach N, Naujock M, Staege S, Eggenschwiler R, Abo-Rady M, Japtok J, Guo W, Hensel N, Reinhardt P, Boeckers TM, Cantz T, Sterneckert J, Van Den Bosch L, Hermann A, Petri S, Wegner F. Altered calcium dynamics and glutamate receptor properties in iPSC-derived motor neurons from ALS patients with C9orf72, FUS, SOD1 or TDP43 mutations. Hum Mol Genet 2020; 28:2835-2850. [PMID: 31108504 DOI: 10.1093/hmg/ddz107] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/02/2019] [Accepted: 05/14/2019] [Indexed: 12/13/2022] Open
Abstract
The fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) is characterized by a profound loss of motor neurons (MNs). Until now only riluzole minimally extends life expectancy in ALS, presumably by inhibiting glutamatergic neurotransmission and calcium overload of MNs. Therefore, the aim of this study was to investigate the glutamate receptor properties and key aspects of intracellular calcium dynamics in induced pluripotent stem cell (iPSC)-derived MNs from ALS patients with C9orf72 (n = 4 cell lines), fused in sarcoma (FUS) (n = 9), superoxide dismutase 1 (SOD1) (n = 3) or transactive response DNA-binding protein 43 (TDP43) (n = 3) mutations as well as healthy (n = 7 cell lines) and isogenic controls (n = 3). Using calcium imaging, we most frequently observed spontaneous transients in mutant C9orf72 MNs. Basal intracellular calcium levels and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced signal amplitudes were elevated in mutant TDP43 MNs. Besides, a majority of mutant TDP43 MNs responded to 3.5-dihydroxyphenylglycine as metabotropic glutamate receptor agonist. Quantitative real-time PCR demonstrated significantly increased expression levels of AMPA and kainate receptors in mutant FUS cells compared to healthy and isogenic controls. Furthermore, the expression of kainate receptors and voltage gated calcium channels in mutant C9orf72 MNs as well as metabotropic glutamate receptors in mutant SOD1 cells was markedly elevated compared to controls. Our data of iPSC-derived MNs from familial ALS patients revealed several mutation-specific alterations in glutamate receptor properties and calcium dynamics that could play a role in ALS pathogenesis and may lead to future translational strategies with individual stratification of neuroprotective ALS treatments.
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Affiliation(s)
- Franziska Bursch
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.,Center of Systems Neuroscience, Hannover, Germany
| | - Norman Kalmbach
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Maximilian Naujock
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Selma Staege
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.,Center of Systems Neuroscience, Hannover, Germany
| | - Reto Eggenschwiler
- Research Group Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, 30625 Hannover, Germany
| | | | - Julia Japtok
- Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany
| | - Wenting Guo
- Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, BE-3000 Leuven, Belgium.,Laboratory of Neurobiology, VIB-Center for Brain & Disease Research, BE-3000 Leuven, Belgium
| | - Niko Hensel
- Institute of Neuroanatomy, Hannover Medical School, 30625 Hanover, Germany
| | | | - Tobias M Boeckers
- Institute of Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany
| | - Tobias Cantz
- Research Group Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, 30625 Hannover, Germany
| | | | - Ludo Van Den Bosch
- Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, BE-3000 Leuven, Belgium.,Laboratory of Neurobiology, VIB-Center for Brain & Disease Research, BE-3000 Leuven, Belgium
| | - Andreas Hermann
- Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany
| | - Susanne Petri
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.,Center of Systems Neuroscience, Hannover, Germany
| | - Florian Wegner
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.,Center of Systems Neuroscience, Hannover, Germany
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36
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Gregory JM, Livesey MR, McDade K, Selvaraj BT, Barton SK, Chandran S, Smith C. Dysregulation of AMPA receptor subunit expression in sporadic ALS post-mortem brain. J Pathol 2019; 250:67-78. [PMID: 31579943 PMCID: PMC6973025 DOI: 10.1002/path.5351] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 09/02/2019] [Accepted: 09/19/2019] [Indexed: 12/12/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is characterised by progressive motor neuron degeneration. Although there are over 40 genes associated with causal monogenetic mutations, the majority of ALS patients are not genetically determined. Causal ALS mutations are being increasingly mechanistically studied, though how these mechanisms converge and diverge between the multiple known familial causes of ALS (fALS) and sporadic forms of ALS (sALS) and furthermore between different neuron types, is poorly understood. One common pathway that is implicated in selective motor neuron death is enhanced α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPAR)-mediated excitoxicity. Specifically, human in vitro and pathological evidence has linked the C9orf72 repeat expansion mutation to a relative increase in the Ca2+ -permeable AMPAR population due to AMPAR subunit dysregulation. Here, we provide the first comparative quantitative assessment of the expression profile of AMPAR subunit transcripts, using BaseScope, in post-mortem lower motor neurons (spinal cord, anterior horn), upper motor neurons (motor cortex) and neurons of the pre-frontal cortex in sALS and fALS due to mutations in SOD1 and C9orf72. Our data indicated that AMPAR dysregulation is prominent in lower motor neurons in all ALS cases. However, sALS and mutant C9orf72 cases exhibited GluA1 upregulation whereas mutant SOD1 cases displayed GluA2 down regulation. We also showed that sALS cases exhibited widespread AMPAR dysregulation in the motor and pre-frontal cortex, though the exact identity of the AMPAR subunit being dysregulated was dependent on brain region. In contrast, AMPAR dysregulation in mutant SOD1 and C9orf72 cases was restricted to lower motor neurons only. Our data highlight the complex dysregulation of AMPAR subunit expression that reflects both converging and diverging mechanisms at play between different brain regions and between ALS cohorts. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jenna M Gregory
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK
| | - Matthew R Livesey
- Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.,Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Karina McDade
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK
| | - Bhuvaneish T Selvaraj
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK
| | - Samantha K Barton
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK
| | - Siddharthan Chandran
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK
| | - Colin Smith
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK
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37
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Norante RP, Peggion C, Rossi D, Martorana F, De Mario A, Lia A, Massimino ML, Bertoli A. ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca 2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model. Int J Mol Sci 2019; 20:E5151. [PMID: 31627428 PMCID: PMC6829245 DOI: 10.3390/ijms20205151] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/26/2019] [Accepted: 10/15/2019] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.
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Affiliation(s)
- Rosa Pia Norante
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
| | - Caterina Peggion
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
| | - Daniela Rossi
- Laboratory for Research on Neurodegenerative Disorders, Istituti Clinici Scientifici Maugeri SpA SB-IRCCS, 27100 Pavia, Italy.
| | - Francesca Martorana
- Laboratory for Research on Neurodegenerative Disorders, Istituti Clinici Scientifici Maugeri SpA SB-IRCCS, 27100 Pavia, Italy.
| | - Agnese De Mario
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
| | - Annamaria Lia
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
| | | | - Alessandro Bertoli
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
- CNR-Neuroscience Institute, University of Padova, 35131 Padova, Italy.
- Padova Neuroscience Center, University of Padova, 35131 Padova, Italy.
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38
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Abstract
Motor neuron disorders are highly debilitating and mostly fatal conditions for which only limited therapeutic options are available. To overcome this limitation and develop more effective therapeutic strategies, it is critical to discover the pathogenic mechanisms that trigger and sustain motor neuron degeneration with the greatest accuracy and detail. In the case of Amyotrophic Lateral Sclerosis (ALS), several genes have been associated with familial forms of the disease, whilst the vast majority of cases develop sporadically and no defined cause can be held responsible. On the contrary, the huge majority of Spinal Muscular Atrophy (SMA) occurrences are caused by loss-of-function mutations in a single gene, SMN1. Although the typical hallmark of both diseases is the loss of motor neurons, there is increasing awareness that pathological lesions are also present in the neighbouring glia, whose dysfunction clearly contributes to generating a toxic environment in the central nervous system. Here, ALS and SMA are sequentially presented, each disease section having a brief introduction, followed by a focussed discussion on the role of the astrocytes in the disease pathogenesis. Such a dissertation is substantiated by the findings that built awareness on the glial involvement and how the glial-neuronal interplay is perturbed, along with the appraisal of this new cellular site for possible therapeutic intervention.
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39
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Bonifacino T, Provenzano F, Gallia E, Ravera S, Torazza C, Bossi S, Ferrando S, Puliti A, Van Den Bosch L, Bonanno G, Milanese M. In-vivo genetic ablation of metabotropic glutamate receptor type 5 slows down disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2019; 129:79-92. [DOI: 10.1016/j.nbd.2019.05.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/19/2019] [Accepted: 05/11/2019] [Indexed: 11/30/2022] Open
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40
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Halpern M, Brennand KJ, Gregory J. Examining the relationship between astrocyte dysfunction and neurodegeneration in ALS using hiPSCs. Neurobiol Dis 2019; 132:104562. [PMID: 31381978 DOI: 10.1016/j.nbd.2019.104562] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 06/28/2019] [Accepted: 07/31/2019] [Indexed: 02/07/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a complex and fatal neurodegenerative disease for which the causes of disease onset and progression remain unclear. Recent advances in human induced pluripotent stem cell (hiPSC)-based models permit the study of the genetic factors associated with ALS in patient-derived neural cell types, including motor neurons and glia. While astrocyte dysfunction has traditionally been thought to exacerbate disease progression, astrocytic dysfunction may play a more direct role in disease initiation and progression. Such non-cell autonomous mechanisms expand the potential targets of therapeutic intervention, but only a handful of ALS risk-associated genes have been examined for their impact on astrocyte dysfunction and neurodegeneration. This review summarizes what is currently known about astrocyte function in ALS and suggests ways in which hiPSC-based models can be used to more effectively study the role of astrocytes in neurodegenerative disease.
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Affiliation(s)
- Madeline Halpern
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America
| | - Kristen J Brennand
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America.
| | - James Gregory
- Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, United States of America.
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41
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Li K, Li J, Zheng J, Qin S. Reactive Astrocytes in Neurodegenerative Diseases. Aging Dis 2019; 10:664-675. [PMID: 31165009 PMCID: PMC6538217 DOI: 10.14336/ad.2018.0720] [Citation(s) in RCA: 261] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 07/20/2018] [Indexed: 12/17/2022] Open
Abstract
Astrocytes, the largest and most numerous glial cells in the central nervous system (CNS), play a variety of important roles in regulating homeostasis, increasing synaptic plasticity and providing neuroprotection, thus helping to maintain normal brain function. At the same time, astrocytes can participate in the inflammatory response and play a key role in the progression of neurodegenerative diseases. Reactive astrocytes are strongly induced by numerous pathological conditions in the CNS. Astrocyte reactivity is initially characterized by hypertrophy of soma and processes, triggered by different molecules. Recent studies have demonstrated that neuroinflammation and ischemia can elicit two different types of reactive astrocytes, termed A1s and A2s. However, in the case of astrocyte reactivity in different neurodegenerative diseases, the recently published research issues remain a high level of conflict and controversy. So far, we still know very little about whether and how the function or reactivity of astrocytes changes in the progression of different neurodegenerative diseases. In this review, we aimed to briefly discuss recent studies highlighting the complex contribution of astrocytes in the process of various neurodegenerative diseases, which may provide us with new prospects for the development of an excellent therapeutic target for neurodegenerative diseases.
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Affiliation(s)
- Kunyu Li
- 1Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jiatong Li
- 1Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jialin Zheng
- 2Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai, China
| | - Song Qin
- 1Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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42
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Franz CK, Joshi D, Daley EL, Grant RA, Dalamagkas K, Leung A, Finan JD, Kiskinis E. Impact of traumatic brain injury on amyotrophic lateral sclerosis: from bedside to bench. J Neurophysiol 2019; 122:1174-1185. [PMID: 31116639 DOI: 10.1152/jn.00572.2018] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, which manifests clinically as progressive weakness. Although several epidemiological studies have found an association between traumatic brain injury (TBI) and ALS, there is not a consensus on whether TBI is an ALS risk factor. It may be that it can cause ALS in a subset of susceptible patients, based on a history of repetitive mild TBI and genetic predisposition. This cannot be determined based on clinical observational studies alone. Better preclinical models are necessary to evaluate the effects of TBI on ALS onset and progression. To date, only a small number of preclinical studies have been performed, mainly in the superoxide dismutase 1 transgenic rodents, which, taken together, have mixed results and notable methodological limitations. The more recent incorporation of additional animal models such as Drosophila flies, as well as patient-induced pluripotent stem cell-derived neurons, should facilitate a better understanding of a potential functional interaction between TBI and ALS.
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Affiliation(s)
- Colin K Franz
- Biologics Laboratory, Shirley Ryan AbilityLab, Chicago, Illinois.,Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, Illinois.,The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Divya Joshi
- Biologics Laboratory, Shirley Ryan AbilityLab, Chicago, Illinois
| | - Elizabeth L Daley
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Rogan A Grant
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kyriakos Dalamagkas
- Department of Physical Medicine and Rehabilitation, McGovern Medical School, TIRR Memorial Hermann, Houston, Texas
| | - Audrey Leung
- Biologics Laboratory, Shirley Ryan AbilityLab, Chicago, Illinois.,Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - John D Finan
- Department of Neurosurgery, NorthShore University HealthSystem, Evanston, Illinois
| | - Evangelos Kiskinis
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.,Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Tischbein M, Baron DM, Lin YC, Gall KV, Landers JE, Fallini C, Bosco DA. The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for GRIA2 mRNA processing. J Biol Chem 2019; 294:10194-10210. [PMID: 31092554 DOI: 10.1074/jbc.ra118.005933] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 05/13/2019] [Indexed: 12/13/2022] Open
Abstract
Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity included TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS). We noted that FUS is translocated through a calcium-dependent mechanism and that its translocation coincides with striking alterations in nucleocytoplasmic transport. Furthermore, glutamate-induced up-regulation of glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type subunit 2 (GRIA2) in neurons depended on FUS expression, consistent with a functional role for FUS in excitotoxic stress. These findings reveal molecular links among prominent factors in neurodegenerative diseases, namely excitotoxicity, disease-associated RBPs, and nucleocytoplasmic transport.
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Affiliation(s)
- Maeve Tischbein
- From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Desiree M Baron
- From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Yen-Chen Lin
- From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Katherine V Gall
- From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - John E Landers
- From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Claudia Fallini
- From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Daryl A Bosco
- From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
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Mahmoud S, Gharagozloo M, Simard C, Gris D. Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release. Cells 2019; 8:E184. [PMID: 30791579 PMCID: PMC6406900 DOI: 10.3390/cells8020184] [Citation(s) in RCA: 399] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 01/26/2023] Open
Abstract
Glutamate is one of the most prevalent neurotransmitters released by excitatory neurons in the central nervous system (CNS); however, residual glutamate in the extracellular space is, potentially, neurotoxic. It is now well-established that one of the fundamental functions of astrocytes is to uptake most of the synaptically-released glutamate, which optimizes neuronal functions and prevents glutamate excitotoxicity. In the CNS, glutamate clearance is mediated by glutamate uptake transporters expressed, principally, by astrocytes. Interestingly, recent studies demonstrate that extracellular glutamate stimulates Ca2+ release from the astrocytes' intracellular stores, which triggers glutamate release from astrocytes to the adjacent neurons, mostly by an exocytotic mechanism. This released glutamate is believed to coordinate neuronal firing and mediate their excitatory or inhibitory activity. Therefore, astrocytes contribute to glutamate homeostasis in the CNS, by maintaining the balance between their opposing functions of glutamate uptake and release. This dual function of astrocytes represents a potential therapeutic target for CNS diseases associated with glutamate excitotoxicity. In this regard, we summarize the molecular mechanisms of glutamate uptake and release, their regulation, and the significance of both processes in the CNS. Also, we review the main features of glutamate metabolism and glutamate excitotoxicity and its implication in CNS diseases.
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Affiliation(s)
- Shaimaa Mahmoud
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
| | - Marjan Gharagozloo
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
| | - Camille Simard
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
| | - Denis Gris
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
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Chandran R, Kumar M, Kesavan L, Jacob RS, Gunasekaran S, Lakshmi S, Sadasivan C, Omkumar R. Cellular calcium signaling in the aging brain. J Chem Neuroanat 2019; 95:95-114. [DOI: 10.1016/j.jchemneu.2017.11.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 09/03/2017] [Accepted: 11/07/2017] [Indexed: 12/21/2022]
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Hoye ML, Regan MR, Jensen LA, Lake AM, Reddy LV, Vidensky S, Richard JP, Maragakis NJ, Rothstein JD, Dougherty JD, Miller TM. Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis. Brain 2018; 141:2561-2575. [PMID: 30007309 PMCID: PMC6113638 DOI: 10.1093/brain/awy182] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 05/12/2018] [Accepted: 05/24/2018] [Indexed: 12/12/2022] Open
Abstract
We recently demonstrated that microRNA-218 (miR-218) is greatly enriched in motor neurons and is released extracellularly in amyotrophic lateral sclerosis model rats. To determine if the released, motor neuron-derived miR-218 may have a functional role in amyotrophic lateral sclerosis, we examined the effect of miR-218 on neighbouring astrocytes. Surprisingly, we found that extracellular, motor neuron-derived miR-218 can be taken up by astrocytes and is sufficient to downregulate an important glutamate transporter in astrocytes [excitatory amino acid transporter 2 (EAAT2)]. The effect of miR-218 on astrocytes extends beyond EAAT2 since miR-218 binding sites are enriched in mRNAs translationally downregulated in amyotrophic lateral sclerosis astrocytes. Inhibiting miR-218 with antisense oligonucleotides in amyotrophic lateral sclerosis model mice mitigates the loss of EAAT2 and other miR-218-mediated changes, providing an important in vivo demonstration of the relevance of microRNA-mediated communication between neurons and astrocytes. These data define a novel mechanism in neurodegeneration whereby microRNAs derived from dying neurons can directly modify the glial phenotype and cause astrocyte dysfunction.
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Affiliation(s)
- Mariah L Hoye
- Department of Neurology, Washington University School of Medicine; St. Louis, MO, USA
| | - Melissa R Regan
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Leah A Jensen
- Department of Neurology, Washington University School of Medicine; St. Louis, MO, USA
| | - Allison M Lake
- Department of Genetics, Washington University School of Medicine; St. Louis, MO, USA
- Department of Psychiatry, Washington University School of Medicine; St. Louis, MO, USA
| | - Linga V Reddy
- Department of Neurology, Washington University School of Medicine; St. Louis, MO, USA
| | - Svetlana Vidensky
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jean-Philippe Richard
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nicholas J Maragakis
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jeffrey D Rothstein
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joseph D Dougherty
- Department of Genetics, Washington University School of Medicine; St. Louis, MO, USA
- Department of Psychiatry, Washington University School of Medicine; St. Louis, MO, USA
| | - Timothy M Miller
- Department of Neurology, Washington University School of Medicine; St. Louis, MO, USA
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Brambilla L, Martorana F, Guidotti G, Rossi D. Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis. Front Neurosci 2018; 12:622. [PMID: 30210286 PMCID: PMC6123379 DOI: 10.3389/fnins.2018.00622] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 08/17/2018] [Indexed: 12/13/2022] Open
Abstract
Astrocytes have emerged as critical elements for the maintenance and function of the central nervous system. The expression on their cell membrane of RAGE and TLR4 receptors makes astrocytes susceptible to High-mobility group box 1 (HMGB1), a nuclear protein typically released in the extracellular milieu by living cells experiencing physiological stress conditions or by damaged cells. Here, we show that the interaction of HMGB1 with normal spinal cord astrocytes induces the astrocytic production of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Multiple investigations suggest a role for HMGB1 in amyotrophic lateral sclerosis (ALS). Yet, no mechanistic information on the implication of HMGB1 signaling in this disorder is currently available. We demonstrate that non-transgenic and transgenic SOD1WT spinal motor neurons exhibit only a basal nucleus-to-cytoplasm shuttling of the HMGB1 protein. Conversely, in SOD1G93A ALS mouse spinal cords, HMGB1 significantly translocates from the nucleus to the cytoplasm of motor neurons, thereby suggesting that it may be eventually released in the extracellular environment during the progression of the disease. We postulate that extracellular HMGB1 can paracrinally interact with the neighboring astrocytes in an attempt to counteract the neurodegenerative process. Yet, at variance with normal cells, SOD1G93A-expressing astrocytes show impaired capacity to raise BDNF and GDNF levels upon HMGB1 stimulation. Our data suggest that HMGB1 have a potential to promote neuroprotective actions by healthy astrocytes. However, this neurotrophic response is disrupted in ALS astrocytes. This indicates that diseased astroglial cells may exacerbate motor neuron degeneration in ALS because of the loss of their neurosupportive functions.
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Affiliation(s)
- Liliana Brambilla
- Laboratory for Research on Neurodegenerative Disorders, IRCCS Istituti Clinici Scientifici Maugeri (ICS Maugeri), Pavia, Italy
| | - Francesca Martorana
- Laboratory for Research on Neurodegenerative Disorders, IRCCS Istituti Clinici Scientifici Maugeri (ICS Maugeri), Pavia, Italy
| | - Giulia Guidotti
- Laboratory for Research on Neurodegenerative Disorders, IRCCS Istituti Clinici Scientifici Maugeri (ICS Maugeri), Pavia, Italy
| | - Daniela Rossi
- Laboratory for Research on Neurodegenerative Disorders, IRCCS Istituti Clinici Scientifici Maugeri (ICS Maugeri), Pavia, Italy
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P2X7 Receptors Mediate CO-Induced Alterations in Gene Expression in Cultured Cortical Astrocytes—Transcriptomic Study. Mol Neurobiol 2018; 56:3159-3174. [DOI: 10.1007/s12035-018-1302-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 08/06/2018] [Indexed: 01/31/2023]
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Van Damme P, Robberecht W, Van Den Bosch L. Modelling amyotrophic lateral sclerosis: progress and possibilities. Dis Model Mech 2018; 10:537-549. [PMID: 28468939 PMCID: PMC5451175 DOI: 10.1242/dmm.029058] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects the motor system and presents with progressive muscle weakness. Most patients survive for only 2-5 years after disease onset, often due to failure of the respiratory muscles. ALS is a familial disease in ∼10% of patients, with the remaining 90% developing sporadic ALS. Over the past decade, major advances have been made in our understanding of the genetics and neuropathology of ALS. To date, around 20 genes are associated with ALS, with the most common causes of typical ALS associated with mutations in SOD1, TARDBP, FUS and C9orf72. Advances in our understanding of the genetic basis of ALS have led to the creation of different models of this disease. The molecular pathways that have emerged from these systems are more heterogeneous than previously anticipated, ranging from protein aggregation and defects in multiple key cellular processes in neurons, to dysfunction of surrounding non-neuronal cells. Here, we review the different model systems used to study ALS and discuss how they have contributed to our current knowledge of ALS disease mechanisms. A better understanding of emerging disease pathways, the detrimental effects of the various gene mutations and the causes underlying motor neuron denegation in sporadic ALS will accelerate progress in the development of novel treatments. Summary: In this Review, Ludo Van Den Bosch and colleagues discuss the different model systems for studying ALS and how they have contributed to our current understanding of the etiology and pathology of this neurodegenerative disease.
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Affiliation(s)
- Philip Van Damme
- KU Leuven, University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience and Disease (LIND), B-3000 Leuven, Belgium.,VIB - Center of Brain & Disease Research, Laboratory of Neurobiology, B-3000 Leuven, Belgium.,University Hospitals Leuven, Department of Neurology, B-3000 Leuven, Belgium
| | - Wim Robberecht
- KU Leuven, University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience and Disease (LIND), B-3000 Leuven, Belgium.,University Hospitals Leuven, Department of Neurology, B-3000 Leuven, Belgium
| | - Ludo Van Den Bosch
- KU Leuven, University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience and Disease (LIND), B-3000 Leuven, Belgium .,VIB - Center of Brain & Disease Research, Laboratory of Neurobiology, B-3000 Leuven, Belgium
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50
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Serio A, Patani R. Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis. Stem Cells 2018; 36:293-303. [PMID: 29235200 DOI: 10.1002/stem.2758] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/18/2017] [Accepted: 12/04/2017] [Indexed: 12/12/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is incurable and devastating. A dearth of therapies has galvanized experimental focus onto the cellular and molecular mechanisms that both initiate and subsequently drive motor neuron degeneration. A traditional view of ALS pathogenesis posits that disease-specific injury to a subtype of neurons is mechanistically cell-autonomous. This "neuron-centric" view has biased past research efforts. However, a wealth of accumulating evidence now strongly implicates non-neuronal cells as being major determinants of ALS. Although animal models have proven invaluable in basic neuroscience research, a growing number of studies confirm fundamental interspecies differences between popular model organisms and the human condition. This may in part explain the failure of therapeutic translation from rodent preclinical models. It follows that integration of a human experimental model using patient-specific induced pluripotent stem cells may be necessary to capture the complexity of human neurodegeneration with fidelity. Integration of enriched human neuronal and glial experimental platforms into the existing repertoire of preclinical models might prove transformational for clinical trial outcomes in ALS. Such reductionist and integrated cross-modal approaches allow systematic elucidation of cell-autonomous and non-cell-autonomous mechanisms of disease, which may then provide novel cellular targets for therapeutic intervention. Stem Cells 2018;36:293-303.
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Affiliation(s)
- Andrea Serio
- Tissue Engineering and Biophotonics Division, Dental Institute, Kings College London, London, United Kingdom
| | - Rickie Patani
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
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