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Perera ND, De Silva S, Tomas D, Cuic B, Turner BJ. Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction. Glia 2025. [PMID: 40401739 DOI: 10.1002/glia.70045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 05/06/2025] [Accepted: 05/12/2025] [Indexed: 05/23/2025]
Abstract
Amyotrophic lateral sclerosis (ALS) is defined by motor neuron death. However, recent research has identified non-cell-autonomous mechanisms, with significant involvement of glia in disease progression. We link previous observations of intracellular protein aggregates in glia to the autophagy pathway, the primary mediator of intracellular degradation of large protein aggregates. While dysfunctional autophagy is reported in ALS motor neurons, pre-clinical and clinical outcomes of autophagy modulators have been inconsistent, indicating the need for a nuanced understanding of autophagy dynamics across CNS cell types and ALS-affected regions. We hypothesized that glial autophagy is defective in ALS, with glial-type-specific dysfunction. To investigate in vivo autophagy dynamics, we intercrossed SOD1G93A mice with transgenic RFP-EGFP-LC3 autophagy reporter mice, enabling the quantification of autophagy degradation, termed flux. Investigation of autophagy dynamics in SOD1 oligodendrocytes, microglia, and astrocytes at key disease stages uncovered useful insights. While oligodendrocytes seemed to mount effective compensatory autophagic responses to combat mutant SOD1, significantly increased autophagy flux was observed in symptomatic spinal microglia and astrocytes in comparison to controls. Symptomatic SOD1 astrocytes displayed greater autophagy dysfunction compared to microglia, with subcellular analysis revealing cell compartment-specific, transient autophagy defects that returned to control levels by end stage. Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation.
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Affiliation(s)
- Nirma D Perera
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
| | - Subhavi De Silva
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
| | - Doris Tomas
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
| | - Brittany Cuic
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
| | - Bradley J Turner
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
- Perron Institute for Neurological and Translational Science, Queen Elizabeth Medical Centre, Nedlands, Western Australia, Australia
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Xin Z, Xin C, Huo J, Liu Q, Dong H, Li X, Liu Y, Li R. Stage-dependent efficacy of short-chain fatty acids in amyotrophic lateral sclerosis: Insights into autophagy and neuroprotection. Life Sci 2025; 374:123686. [PMID: 40348172 DOI: 10.1016/j.lfs.2025.123686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/23/2025] [Accepted: 05/01/2025] [Indexed: 05/14/2025]
Abstract
AIMS Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options. Previously, we have shown that a combination of multiple probiotic strains can regulate intestinal flora, increase serum short-chain fatty acids (SCFAs), reduce abnormal protein accumulation in the spinal cord, and protect neurons. It is necessary to explore the mechanism to provide therapeutic targets for ALS. MATERIALS AND METHODS This study utilizes live cell imaging, mouse behavioral research, immunofluorescence, Electron microscopy, Western Blot, and polymerase chain reaction to explore the impact of various SCFAs on ALS animal and cell models, as well as their underlying mechanisms. KEY FINDINGS We found SCFAs, including butyrate and propionate can increase the levels of acetylated histones, enhance the expression of autophagy-related genes and regulate autophagy, leading to a decrease in abnormal SOD1 aggregation, reduction of cell damage, and enhancement of cell proliferation in NSC34-SOD1G93A cells. Furthermore, systemic administration of butyrate and propionate can regulate autophagy, reduce SOD1 aggregation, and protect spinal cord neurons in SOD1G93A mice. However, these favorable effects of butyrate and propionate are greatly decreased at later stages of the disease process in SOD1G93A mice. SIGNIFICANCE Our study revealed that the positive impact of SCFAs in autophagy could be a promising focus for ALS therapy. However, this effect might have different impacts in different stages of ALS.
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Affiliation(s)
- Zikai Xin
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China; Department of Neurology, Tianjin Huanhu Hospital, Tianjin, PR China
| | - Cheng Xin
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China
| | - Jia Huo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China
| | - Qi Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China
| | - Hui Dong
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China
| | - Xin Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China
| | - Yaling Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China.
| | - Rui Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, PR China; Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei 050000, PR China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei 050000, PR China.
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Vaage AM, Holmøy T, Dahl J, Stigum H, Meyer HE, Nakken O. Statin Use and Amyotrophic Lateral Sclerosis Survival: A Population-Based Cohort Study. Eur J Neurol 2025; 32:e70095. [PMID: 40034089 PMCID: PMC11876845 DOI: 10.1111/ene.70095] [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: 01/03/2025] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND Dyslipidemia is common in amyotrophic lateral sclerosis (ALS). Statin use has been associated with both favorable and poor prognoses. We assessed whether statin use affects ALS survival. METHODS We linked four Norwegian health surveys (1972-2003) with mandatory national registries to obtain information on premorbid health, ALS diagnosis, and death. Using the Norwegian Prescribed Drug Registry, we identified participants who had dispensed statins pre- and post-diagnosis. We first compared pre-diagnosis statin discontinuation rates between ALS patients and matched controls. Flexible parametric models were then fitted to estimate the relationship between statin use and survival time in ALS, using restricted mean survival time and hazard ratio (HR) as effect measures. RESULTS A total of 524 patients (43% female) with ALS were included. Mean time from ALS diagnosis to death or end of study was 2.0 (SD 2.1) years. A substantial proportion of statin users (21%) discontinued statins during the year leading up to diagnosis. This group was characterized by poorer ALS prognosis compared to those adhering to statins and were included as statin users in our analysis. After adjusting for sex, age, birth year, riluzole use and premorbid smoking status, body mass index, and total cholesterol levels, statin use was not associated with ALS survival. The estimated mean survival difference comparing statin users to non-users was 0.74 (95% CI -5.98 to 7.47) months, corresponding to a HR of 0.97 (95% CI 0.77-1.23). CONCLUSION Statin use was not associated with ALS survival, suggesting that statins should not routinely be discontinued in ALS.
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Affiliation(s)
- Anders Myhre Vaage
- Department of NeurologyAkershus University HospitalLørenskogNorway
- Institute of Clinical MedicineUniversity of OsloOsloNorway
| | - Trygve Holmøy
- Department of NeurologyAkershus University HospitalLørenskogNorway
- Institute of Clinical MedicineUniversity of OsloOsloNorway
| | - Jesper Dahl
- Department of Infection Control and VaccinesNorwegian Institute of Public HealthOsloNorway
| | - Hein Stigum
- Department of Community Medicine and Global HealthUniversity of OsloOsloNorway
| | - Haakon E. Meyer
- Department of Community Medicine and Global HealthUniversity of OsloOsloNorway
- Department of Physical Health and AgeingNorwegian Institute of Public HealthOsloNorway
| | - Ola Nakken
- Department of NeurologyAkershus University HospitalLørenskogNorway
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Wu Y, Zhang Y, Zheng Q, Wang Q, Fang X, Zhu Z, Lu J, Sun D. Myocardial dysfunction caused by MyBPC3 P459fs mutation in hypertrophic cardiomyopathy: evidence from multi-omics approaches and super-resolution imaging. Front Cardiovasc Med 2025; 12:1529921. [PMID: 40083819 PMCID: PMC11903464 DOI: 10.3389/fcvm.2025.1529921] [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: 11/20/2024] [Accepted: 02/07/2025] [Indexed: 03/16/2025] Open
Abstract
Introduction Mutations in the sarcomere protein, particularly in cardiac myosin binding protein C gene (MyBPC3), were the most frequent genetic cause of hypertrophic cardiomyopathy (HCM). The pathogenic MyBPC3 P459fs mutation has been reported in HCM patients. However, there was limited knowledge of the structure-function relationships and potential pathways in clinical HCM with MyBPC3 P459fs mutation. Methods We used multi-omics approaches and super-resolution imaging to explore the effects of MyBPC3 P459fs mutation on humans and cells. HCM patients carrying MyBPC3 P459fs mutation (MyBPC3-P459fs HCMs) and healthy controls (HCs) were evaluated for myocardial function using both conventional and advanced echocardiography. In parallel, H9C2 myocardial cells infected with either MyBPC3 P459fs mutation (P459fs cells) or its wild type (WT cells) were investigated for myocardial fiber formation and the potential pathways behind this using super-resolution imaging and metabolomics and proteomics. Results First, conventional and advanced echocardiography showed that MyBPC3-P459fs HCMs exhibited left ventricular diastolic and systolic dysfunction. Subsequently, super-resolution imaging indicated that P459fs cells formed fewer and shorter myocardial fibers in the cytoplasm compared to WT cells. Moreover, our metabolomic and proteomic data suggested several key components of mitochondrial membrane integrity, myocardial remodeling, myocardial energy metabolism, oxidative stress, inflammation, and actin binding capacity were significantly altered in response to P459fs mutation. Conclusions This investigation indicated myocardial dysfunction and myocardial fiber disarray in clinical HCMs with MyBPC3 P459fs mutation and added potential pathways underlying this. These findings provided a link between the observed structural and functional disorders in MyBPC3 P459fs mutation and its onset of HCM pathogenesis and might have a significant translational contribution to effective treatment in HCM patients with MyBPC3 P459fs mutation.
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Affiliation(s)
- Yupeng Wu
- Department of Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
- Department of Neurosurgery, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
| | - Yuzhu Zhang
- Department of Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
| | - Qirui Zheng
- Department of Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
| | - Qiyuan Wang
- Department of Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
| | - Xingyu Fang
- Department of Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
| | - Zaihan Zhu
- Department of Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
| | - Jing Lu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Key Laboratory of Flavor Chemistry, School of Food and Health, Beijing Technology and Business University, Beijing, China
| | - Dandan Sun
- Department of Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Ultrasound, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, China
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Luo S, Wang X, Ma B, Liu D, Li L, Wang L, Ding N, Zou L, Wang J, Pan J, Sang D, Zhou H, Qu H, Lu Y, Yang L. Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation. BIOMOLECULES & BIOMEDICINE 2025; 25:632-647. [PMID: 39569650 PMCID: PMC12010976 DOI: 10.17305/bb.2024.11218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/14/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.
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Affiliation(s)
- Song Luo
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Xiaorui Wang
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Bo Ma
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Dongliang Liu
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Li Li
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Lijin Wang
- Department of Psychiatry, Bengbu Medical University, Bengbu, China
| | - Ning Ding
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Liangyu Zou
- Department of Neurology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Jie Wang
- International Medical Center (Department of Geriatric Medicine), Shenzhen University General Hospital, Shenzhen, China
| | - Jialin Pan
- Department of Internal Medicine, Second People’s Hospital, Longgang District, Shenzhen, China
| | - Daoqian Sang
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Huadong Zhou
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Hongdang Qu
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Yi Lu
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Lijuan Yang
- Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
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Yang J, Tian M, Zhang L, Xin C, Huo J, Liu Q, Dong H, Li R, Liu Y. Assessment of Rab geranylgeranyltransferase subunit beta in amyotrophic lateral sclerosis. Front Neurol 2024; 15:1447461. [PMID: 39224887 PMCID: PMC11366579 DOI: 10.3389/fneur.2024.1447461] [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: 06/11/2024] [Accepted: 08/01/2024] [Indexed: 09/04/2024] Open
Abstract
Introduction Geranylgeranyltransferase Subunit Beta (RABGGTB) was expressed at higher levels in patients with Amyotrophic lateral sclerosis (ALS) compared with healthy controls. This study aims to observe the expression of RABGGTB in different cells from patients with ALS and different diseases. Methods In this case-control study, we collected peripheral blood from patients with ALS and healthy controls, and compared the expression of RABGGTB in natural killer cells (NK), T cells and B cells between patients with ALS and healthy controls by flow cytometry. And compared the expression of RABGGTB in monocytes and monocyte-derived macrophages from patients with ALS, Parkinson's disease (PD), acute cerebrovascular disease (ACVD), and healthy controls by flow cytometry and immunofluorescence. Then flow cytometry was used to detect the expression of RABGGTB in monocytes from SOD1G93A mice and WT mice. Results The expression of RABGGTB was not significantly changed in NK cells, cytotoxic T cells (CTL), helper T cells (Th), regulatory T cells (Treg), and B cells from patients with ALS compared to healthy controls. And the expression of RABGGTB in monocytes and monocyte-derived macrophages was higher in the ALS group than in the PD, ACVD and control group. The expression of RABGGTB was significantly higher in monocytes of SOD1G93A mice compared to WT mice. Conclusion These findings suggest that RABGGTB expression was increased in monocytes and monocyte-derived macrophages from patients with ALS, not in NK, CTL, Th, Treg, and B cells. Future studies are needed to find the clinical implication of RABGGTB in ALS.
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Affiliation(s)
- Jing Yang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Mei Tian
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Lei Zhang
- Department of Emergency, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Cheng Xin
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Jia Huo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Qi Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Hui Dong
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Rui Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Yaling Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
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Imtiaz A, Shimonaka S, Uddin MN, Elahi M, Ishiguro K, Hasegawa M, Hattori N, Motoi Y. Selection of lansoprazole from an FDA-approved drug library to inhibit the Alzheimer's disease seed-dependent formation of tau aggregates. Front Aging Neurosci 2024; 16:1368291. [PMID: 38633982 PMCID: PMC11022852 DOI: 10.3389/fnagi.2024.1368291] [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: 01/10/2024] [Accepted: 03/15/2024] [Indexed: 04/19/2024] Open
Abstract
The efficacy of current treatments is still insufficient for Alzheimer's disease (AD), the most common cause of Dementia. Out of the two pathological hallmarks of AD amyloid-β plaques and neurofibrillary tangles, comprising of tau protein, tau pathology strongly correlates with the symptoms of AD. Previously, screening for inhibitors of tau aggregation that target recombinant tau aggregates have been attempted. Since a recent cryo-EM analysis revealed distinct differences in the folding patterns of heparin-induced recombinant tau filaments and AD tau filaments, this study focused on AD seed-dependent tau aggregation in drug repositioning for AD. We screened 763 compounds from an FDA-approved drug library using an AD seed-induced tau aggregation in SH-SY5Y cell-based assay. In the first screening, 180 compounds were selected, 72 of which were excluded based on the results of lactate dehydrogenase assay. In the third screening with evaluations of soluble and insoluble tau, 38 compounds were selected. In the fourth screening with 3 different AD seeds, 4 compounds, lansoprazole, calcipotriene, desogestrel, and pentamidine isethionate, were selected. After AD seed-induced real-time quaking-induced conversion, lansoprazole was selected as the most suitable drug for repositioning. The intranasal administration of lansoprazole for 4 months to AD seed-injected mice improved locomotor activity and reduced both the amount of insoluble tau and the extent of phosphorylated tau-positive areas. Alanine replacement of the predicted binding site to an AD filament indicated the involvement of Q351, H362, and K369 in lansoprazole and C-shaped tau filaments. These results suggest the potential of lansoprazole as a candidate for drug repositioning to an inhibitor of tau aggregate formation in AD.
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Affiliation(s)
- Ahmed Imtiaz
- Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Department of Neurology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Shotaro Shimonaka
- Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Mohammad Nasir Uddin
- Department of Biochemistry & Molecular Biology, Faculty of Life Science, Mawlana Bhashani Science & Technology University, Tangail, Bangladesh
| | - Montasir Elahi
- Center for Birth Defect Research, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Koichi Ishiguro
- Department of Neurology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Masato Hasegawa
- Department of Brain and Neuroscience, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan
| | - Nobutaka Hattori
- Department of Neurology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Yumiko Motoi
- Medical Center for Dementia, Juntendo University Hospital, Bunkyo-ku, Tokyo, Japan
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Ma H, Huo J, Xin C, Yang J, Liu Q, Dong H, Li R, Liu Y. RABGGTB plays a critical role in ALS pathogenesis. Brain Res Bull 2024; 206:110833. [PMID: 38042502 DOI: 10.1016/j.brainresbull.2023.110833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/25/2023] [Accepted: 11/28/2023] [Indexed: 12/04/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unknown causes, which mainly affects motor neurons in the anterior horn of the spinal cord, brain stem, and cerebral cortex, also known as motor neuron disease. An important pathological feature of ALS is the formation of aggregates of mutant SOD1 protein, CTF25 of TDP-43, or other abnormal proteins in motor neurons, which require autophagy for degradation. Protein prenylation is known to participate in membrane association and proper localization of proteins. RABGGTB is the β subunit of GGTase II (one of the prenyltransferases) that can regulate autophagy via Rab7 geranylgeranylation. In this study, we overexpressed RABGGTB via lentiviral transfection in NSC34-hSOD1G93A and TDP-43 cells. Overexpression of RABGGTB improved ALS cell proliferation by facilitating autophagosome-lysosome fusion. Furthermore, the abnormal aggregation of SOD1 protein was reduced. This indicates that protein prenylation is important for the proliferation and autophagy of cells autophagy. Enhanced autophagy has been observed in two of the most widely used ALS cell models. These findings indicate the widespread applicability of prenylation in ALS. In summary, overexpression of RABGGTB improved the geranylgeranylation of the Rab7 protein and had a positive effect on cells. These findings provide insights into the development of a novel therapeutic strategy for ALS.
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Affiliation(s)
- Haiyang Ma
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Jia Huo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Cheng Xin
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Jing Yang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Qi Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Hui Dong
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Rui Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China.
| | - Yaling Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China; Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China.
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9
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Ahmad F, Karim A, Khan J, Qaisar R. Statin Therapy Induces Gut Leakage and Neuromuscular Disjunction in Patients With Chronic Heart Failure. J Cardiovasc Pharmacol 2023; 82:189-195. [PMID: 37381157 DOI: 10.1097/fjc.0000000000001445] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
ABSTRACT Statins are commonly used to limit the risk of cardiovascular diseases, including ischemic heart attack and stroke. However, treatment often leads to myopathy and muscle weakness. Therefore, a better understanding of underlying pathomechanism is needed to improve the clinical outcomes. Here, we assessed the physical performance, including handgrip strength (HGS), gait speed (GS), and short physical performance battery, in 172 patients diagnosed with chronic heart failure (CHF) treated with (n = 50) or without (n = 122) statin and 59 controls. The plasma biomarkers, including sarcopenia marker C-terminal agrin fragment-22 (CAF22), intestinal barrier integrity marker zonulin, and C-reactive protein (CRP), were measured and correlated with the physical performance of patients. The HGS, short physical performance battery scores, and GS were significantly compromised in patients with CHF versus controls. Irrespective of etiology, significant elevation of plasma CAF22, zonulin, and CRP was observed in patients with CHF. There were strong inverse correlations of CAF22 with HGS (r 2 = 0.34, P < 0.0001), short physical performance battery scores (r 2 = 0.08, P = 0.0001), and GS (r 2 = 0.143, P < 0.0001). Strikingly, CAF22 and zonulin were positively correlated with each other (r 2 = 0.10, P = 0.0002) and with the level of CRP in patients with CHF. Further investigations revealed a significant induction of CAF22, zonulin, and CRP in patients with CHF taking statin versus nonstatin group. Consistently, HGS and GS were significantly lower in the statin versus nonstatin CHF patients' group. Collectively, statin therapy adversely affects the neuromuscular junction and intestinal barrier, which potentially induces systemic inflammation and physical disability in patients with CHF. Further prospective confirmation of the findings is required in a well-controlled study.
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Affiliation(s)
- Firdos Ahmad
- Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | - Asima Karim
- Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Javaidullah Khan
- Department of Cardiology, Post Graduate Medical Institute, Hayatabad Medical Complex, Peshawar, Pakistan; and
| | - Rizwan Qaisar
- Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
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10
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Morimoto S, Takahashi S, Ito D, Daté Y, Okada K, Kato C, Nakamura S, Ozawa F, Chyi CM, Nishiyama A, Suzuki N, Fujimori K, Kondo T, Takao M, Hirai M, Kabe Y, Suematsu M, Jinzaki M, Aoki M, Fujiki Y, Sato Y, Suzuki N, Nakahara J, Okano H. Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery. Cell Stem Cell 2023; 30:766-780.e9. [PMID: 37267913 DOI: 10.1016/j.stem.2023.04.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 01/12/2023] [Accepted: 04/24/2023] [Indexed: 06/04/2023]
Abstract
iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.
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Affiliation(s)
- Satoru Morimoto
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Shinichi Takahashi
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology and Stroke, Saitama Medical University International Medical Center, Saitama 350-1298, Japan
| | - Daisuke Ito
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yugaku Daté
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kensuke Okada
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Chris Kato
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Shiho Nakamura
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Fumiko Ozawa
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Chai Muh Chyi
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Keio University Global Research Institute, Tokyo 108-8345, Japan
| | - Ayumi Nishiyama
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Naoki Suzuki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Koki Fujimori
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tosho Kondo
- Research Center of Neurology, ONO Pharmaceutical Co., Ltd., Osaka 541-8564, Japan
| | - Masaki Takao
- Department of Clinical Laboratory, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-0031, Japan; Department of Neurology, Mihara Memorial Hospital, Isesaki, Gunmma 372-0006, Japan
| | - Miwa Hirai
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yasuaki Kabe
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masahiro Jinzaki
- Department of Radiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masashi Aoki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Yuto Fujiki
- Keio University Hospital Clinical and Translational Research Center, Tokyo 160-8582, Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Norihiro Suzuki
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Jin Nakahara
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
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11
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Qaisar R, Karim A, Muhammad T, Alkahtani SA, Kamli H, Ahmad F. Degradation of neuromuscular junction contributes to muscle weakness but not physical compromise in chronic obstructive pulmonary disease patients taking lipids-lowering medications. Respir Med 2023:107298. [PMID: 37245649 DOI: 10.1016/j.rmed.2023.107298] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/19/2023] [Accepted: 05/26/2023] [Indexed: 05/30/2023]
Abstract
OBJECTIVES The relevant data about the effects and the associated mechanisms of statins on muscle strength and physical capacity is inconsistent. We investigated the potential contribution of neuromuscular junction (NMJ) degradation to muscle weakness and physical compromise in patients with chronic obstructive pulmonary disease (COPD) on statins. METHOD We recruited male COPD patients (age range = 63-75 years, n = 150) as nonusers (n = 71) and users of statin medications (n = 79) along with age-matched controls (n = 76). The COPD patients were evaluated at baseline and one year later. The data about handgrip strength (HGS), body composition, short physical performance battery (SPPB), and plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ disintegration was collected at two time points. RESULTS We observed lower HGS, SPPB scores, and higher CAF22 levels in all COPD patients than controls, irrespective of the treatment status (all p < 0.05). Statins further reduced HGS and elevated CAF22 in COPD patients (both p < 0.05). The decline in SPPB was relatively modest in statin users (≈3.7%, p = 0.032) than in nonusers (≈8.7%, p = 0.002). The elevated plasma CAF22 exhibited robust negative correlations with a reduction in HGS but not with SPPB in COPD patients taking statins. We also found a reduction in markers of inflammation and no increase in oxidative stress markers following statin use in COPD patients. CONCLUSION Altogether, statin-induced NMJ degradation exacerbates muscle decline but does not contribute to physical compromise in COPD patients.
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Affiliation(s)
- Rizwan Qaisar
- Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Cardiovascular Research Group, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
| | - Asima Karim
- Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Tahir Muhammad
- Department of Biochemistry, Gomal Medical College, Gomal University, Dera Ismail Khan, 30130, Pakistan
| | - Shaea A Alkahtani
- Exercise Physiology Department, College of Sport Sciences and Physical Activity, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Hossam Kamli
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia
| | - Firdos Ahmad
- Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Cardiovascular Research Group, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, 59911, United Arab Emirates
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12
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Wang L, Wang T, Wen S, Song R, Zou H, Gu J, Liu X, Bian J, Liu Z, Yuan Y. Puerarin Prevents Cadmium-Induced Neuronal Injury by Alleviating Autophagic Dysfunction in Rat Cerebral Cortical Neurons. Int J Mol Sci 2023; 24:ijms24098328. [PMID: 37176033 PMCID: PMC10179714 DOI: 10.3390/ijms24098328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 04/23/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Autophagic dysfunction is one of the main mechanisms of cadmium (Cd)-induced neurotoxicity. Puerarin (Pue) is a natural antioxidant extracted from the medicinal and edible homologous plant Pueraria lobata. Studies have shown that Pue has neuroprotective effects in a variety of brain injuries, including Cd-induced neuronal injury. However, the role of Pue in the regulation of autophagy to alleviate Cd-induced injury in rat cerebral cortical neurons remains unclear. This study aimed to elucidate the protective mechanism of Pue in alleviating Cd-induced injury in rat cerebral cortical neurons by targeting autophagy. Our results showed that Pue alleviated Cd-induced injury in rat cerebral cortical neurons in vitro and in vivo. Pue activates autophagy and alleviates Cd-induced autophagic blockade in rat cerebral cortical neurons. Further studies have shown that Pue alleviates the Cd-induced inhibition of autophagosome-lysosome fusion, as well as the inhibition of lysosomal degradation. The specific mechanism is related to Pue alleviating the inhibition of Cd on the expression levels of the key proteins Rab7, VPS41, and SNAP29, which regulate autophagosome-lysosome fusion, as well as the lysosome-related proteins LAMP2, CTSB, and CTSD. In summary, these results indicate that Pue alleviates Cd-induced autophagic dysfunction in rat cerebral cortical neurons by alleviating autophagosome-lysosome fusion dysfunction and lysosomal degradation dysfunction, thereby alleviating Cd-induced neuronal injury.
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Affiliation(s)
- Li Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Tao Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Shuangquan Wen
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Xuezhong Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
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13
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Kreple CJ, Searles Nielsen S, Schoch KM, Shen T, Shabsovich M, Song Y, Racette BA, Miller TM. Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model. Ann Neurol 2023; 93:881-892. [PMID: 36627836 PMCID: PMC11971731 DOI: 10.1002/ana.26600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 12/12/2022] [Accepted: 01/08/2023] [Indexed: 01/12/2023]
Abstract
OBJECTIVE The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. METHODS We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. RESULTS We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. INTERPRETATION Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.
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Affiliation(s)
- Collin J Kreple
- Department of Neurology, Washington University School of Medicine, St. Louis, MO
| | | | - Kathleen M Schoch
- Department of Neurology, Washington University School of Medicine, St. Louis, MO
| | - Tao Shen
- Department of Neurology, Washington University School of Medicine, St. Louis, MO
| | - Mark Shabsovich
- Department of Neurology, Washington University School of Medicine, St. Louis, MO
| | - Yizhe Song
- Department of Neurology, Washington University School of Medicine, St. Louis, MO
| | - Brad A Racette
- Department of Neurology, Washington University School of Medicine, St. Louis, MO
- Barrow Neurological Institute, Phoenix, AZ
- School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
| | - Timothy M Miller
- Department of Neurology, Washington University School of Medicine, St. Louis, MO
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14
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Gao T, Huo J, Xin C, Yang J, Liu Q, Dong H, Li R, Liu Y. Protective effects of intrathecal injection of AAV9-RabGGTB-GFP+ in SOD1G93A mice. Front Aging Neurosci 2023; 15:1092607. [PMID: 36967828 PMCID: PMC10036913 DOI: 10.3389/fnagi.2023.1092607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/24/2023] [Indexed: 03/12/2023] Open
Abstract
IntroductionAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that widely affects motor neurons of the CNS. About 20% of patients with ALS have familial ALS (fALS). One of the classic models of ALS are SOD1G93A mice. Misfolded SOD1 protein can be overexpressed in motor neurons, which results in progressive paralysis of the limbs of mice. There is still no effective treatment for ALS. In recent years, the treatment of ALS by regulating autophagy has become a research hotspot. Autophagy obstacles have been confirmed to be one of the early pathological events of ALS. Rab7 is a member of the Ras superfamily and plays a key role in the late stage of autophagy. In our previous studies, we found that prenoylation of Rab7 was inhibited in the ALS model. Prenylation is a post-translational modification in which farnesyl or geranylgeranyl groups are covalently linked to target proteins. Based on these findings, we proposed the novel idea that the regulation of RabGGTB (the β-subunit of RabGGTase) mediated prenylation modification of Rab7, and that this can be used as a prevention and treatment of ALS associated with abnormal protein accumulation.MethodsIn the present study, RabGGTB was overexpressed in mouse spinal cord motoneurons by using adeno-associated virus as vector. Then immunofluorescence quantitative analysis was used for pathological study. The body weight, footprint analysis, the accelerating rotarod test, and neurological deficits score were used to evaluate animal behavior.ResultsOur results show that the protein level of RabGGTB was significantly increased in the lumbar and thoracic regions of spinal cord motoneurons of injected mice. Furthermore, the onset time and survival time of SOD1G93A mice injected with AAV9-RabGGTB-GFP+ were delayed compared with those of mice without overexpression. At the same time, we also observed a decrease in SOD1 misfolded and glial overactivation in the lumbar spinal cord of these SOD1G93A mice.ConclusionThe findings reported here show that RabGGTB plays a significant role in the pathogenesis of SOD1G93A mice and with great therapeutic potential for reducing abnormal aggregation of SOD1 in ALS.
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Affiliation(s)
- Tianchu Gao
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Jia Huo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Cheng Xin
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Jing Yang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Qi Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Hui Dong
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Rui Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
- *Correspondence: Rui Li, ; Yaling Liu,
| | - Yaling Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- The Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, Shijiazhuang, Hebei, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, China
- *Correspondence: Rui Li, ; Yaling Liu,
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15
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Zhang Y, Chen L, Li Z, Li D, Wu Y, Guo Y. Endothelin-1, over-expressed in SOD1G93A mice, aggravates injury of NSC34-hSOD1G93A cells through complicated molecular mechanism revealed by quantitative proteomics analysis. Front Cell Neurosci 2022; 16:1069617. [DOI: 10.3389/fncel.2022.1069617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022] Open
Abstract
Endothelin-1 (ET-1), a secreted signaling peptide, is suggested to be involved in multiple actions in various tissues including the brain, but its role in amyotrophic lateral sclerosis (ALS) remains unknown. In this study, we detected the expression changes as well as the cellular localization of ET-1, endothelin A (ET-A) and endothelin B (ET-B) receptors in spinal cord of transgenic SOD1-G93A (TgSOD1-G93A) mice, which showed that the two ET receptors (ET-Rs) expressed mainly on neurons and decreased as the disease progressed especially ET-B, while ET-1 expression was up-regulated and primarily localized on astrocytes. We then explored the possible mechanisms underlying the effect of ET-1 on cultured NSC34-hSOD1G93A cell model. ET-1 showed toxic effect on motor neurons (MNs), which can be rescued by the selective ET-A receptor antagonist BQ-123 or ET-B receptor antagonist BQ-788, suggesting that clinically used ET-Rs pan-antagonist could be a potential strategy for ALS. Using proteomic analysis, we revealed that 110 proteins were differentially expressed in NSC34-hSOD1G93A cells after ET-1 treatment, of which 54 were up-regulated and 56 were down-regulated. Bioinformatic analysis showed that the differentially expressed proteins (DEPs) were primarily enriched in hippo signaling pathway-multiple species, ABC transporters, ErbB signaling pathway and so on. These results provide further insights on the potential roles of ET-1 in ALS and present a new promising therapeutic target to protect MNs of ALS.
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16
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Weisskopf MG, Levy J, Dickerson AS, Paganoni S, Leventer-Roberts M. Statin Medications and Amyotrophic Lateral Sclerosis Incidence and Mortality. Am J Epidemiol 2022; 191:1248-1257. [PMID: 35333291 PMCID: PMC9393061 DOI: 10.1093/aje/kwac054] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 01/26/2023] Open
Abstract
Studies of statins and amyotrophic lateral sclerosis (ALS) incidence and survival have had conflicting findings possibly related to difficulties with confounding by indication. We considered potency of statins used and duration of use to explore confounding by indication. Within the Clalit Health Services in Israel, we identified 948 ALS case patients from 2004 through 2017 and matched them with 1,000 control subjects each. Any statin use up to 3 years before ALS onset was not associated with ALS incidence but was associated with a reduced hazard ratio (HR) for death. Odds of ALS did not vary by statin potency, but use of only lower-potency statins was associated with longer survival (HR = 0.82, 95% CI: 0.68, 0.98), whereas the association with higher-potency statins was null compared with those case patients who did not use statins. However, duration of statin use appeared to account for these findings. Those who used statins only up to 3 years had longer survival (HR = 0.77, 95% CI: 0.61, 0.96) than did case patients who did not use statins, but those who used statins for >3 years did not. Although other explanations are possible, these findings could suggest a protective effect of statins on ALS survival that is partially masked by a worse prognosis from underlying reasons for taking statins that deserves further exploration.
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Affiliation(s)
- Marc G Weisskopf
- Correspondence to Marc Weisskopf, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Building 1, Suite 1402, Boston, MA 02115 (e-mail: )
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Yang C, Zhang X. Research progress on vesicular trafficking in amyotrophic lateral sclerosis. Zhejiang Da Xue Xue Bao Yi Xue Ban 2022; 51:380-387. [PMID: 36161717 PMCID: PMC9511476 DOI: 10.3724/zdxbyxb-2022-0024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/10/2022] [Indexed: 06/16/2023]
Abstract
Vesicular trafficking is a basic physiological process by which vesicles transport materials between cells and environment (intercellular transport) and between different cellular compartments (intracellular trafficking). In recent years, more and more evidences have suggested that vesicular trafficking dysfunction plays a key role in pathogenesis of neurodegenerative diseases. Abnormal vesicular trafficking promotes the propagation of misfolded proteins by mechanisms involving endocytosis, endosomal-lysosomal pathway, endosomal escape and exosome release, leading to further acceleration of disease progression. Amyotrophic lateral sclerosis (ALS), as a neurodegenerative disease, is characterized by the selective death of upper and lower motor neurons. A variety of causative genes for ALS have been implicated in vesicle trafficking dysfunction, such as C9ORF72, TARDBP and SOD1. Therefore, the aggregation and propagation of misfolded proteins may be prevented through regulation of vesicle trafficking-related proteins, thus delay the progression of ALS. A more in-depth understanding of vesicular trafficking in ALS will be helpful in revealing the mechanism and clinical treatment of ALS. This review focuses on molecular mechanisms of vesicular trafficking in ALS, to provide reference for exploring new therapeutic strategies.
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Zhang Q, Qu H, Chen Y, Luo X, Chen C, Xiao B, Ding X, Zhao P, Lu Y, Chen AF, Yu Y. Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis. Front Cell Dev Biol 2022; 10:806081. [PMID: 35309902 PMCID: PMC8927716 DOI: 10.3389/fcell.2022.806081] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/03/2022] [Indexed: 01/25/2023] Open
Abstract
As one of the cornerstones of clinical cardiovascular disease treatment, statins have an extensive range of applications. However, statins commonly used have side reactions, especially muscle-related symptoms (SAMS), such as muscle weakness, pain, cramps, and severe condition of rhabdomyolysis. This undesirable muscular effect is one of the chief reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. Moreover, the underlying mechanism of muscle cell damage is still unclear. Here, we discovered that ferroptosis, a programmed iron-dependent cell death, serves as a mechanism in statin-induced myopathy. Among four candidates including atorvastatin, lovastatin, rosuvastatin, and pravastatin, only atorvastatin could lead to ferroptosis in human cardiomyocytes (HCM) and murine skeletal muscle cells (C2C12), instead of human umbilical vein endothelial cell (HUVEC). Atorvastatin inhibits HCM and C2C12 cell viability in a dose-dependent manner, accompanying with significant augmentation in intracellular iron ions, reactive oxygen species (ROS), and lipid peroxidation. A noteworthy investigation found that those alterations particularly occurred in mitochondria and resulted in mitochondrial dysfunction. Biomarkers of myocardial injury increase significantly during atorvastatin intervention. However, all of the aforementioned enhancement could be restrained by ferroptosis inhibitors. Mechanistically, GSH depletion and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPx4), and xCT cystine–glutamate antiporter (the main component is SLC7A11) are involved in atorvastatin-induced muscular cell ferroptosis and damage. The downregulation of GPx4 in mitochondria-mediated ferroptosis signaling may be the core of it. In conclusion, our findings explore an innovative underlying pathophysiological mechanism of atorvastatin-induced myopathy and highlight that targeting ferroptosis serves as a protective strategy for clinical application.
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Affiliation(s)
- Qi Zhang
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hang Qu
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yinghui Chen
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xueyang Luo
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chong Chen
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bing Xiao
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaowei Ding
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Pengjun Zhao
- Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanan Lu
- Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Alex F. Chen
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Yu Yu, ; Alex F. Chen,
| | - Yu Yu
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Yu Yu, ; Alex F. Chen,
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Nabizadeh F, Balabandian M, Sharafi AM, Ghaderi A, Rostami MR, Naser Moghadasi A. Statins and risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis. Acta Neurol Belg 2021; 122:979-986. [PMID: 34322852 DOI: 10.1007/s13760-021-01753-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/12/2021] [Indexed: 12/16/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a paralytic, heterogeneous and progressive disease characterized by the degeneration of both upper and lower motor neurons. Several studies about the effects of statins drug on the risk of ALS showed contradictory results and evidence for this is inconclusive. So we aimed to perform a meta-analysis on previous studies to clarify the association between statin use and risk of ALS. The databases including PubMed, Scopus, and Web of science were searched in February 2021 for studies that reported the association between statin use and risk of ALS. The eligible studies had to provide a report on the effect of statin and the incidence of ALS while comparing it to the control group. Articles that had low statin exposure time, the absence of a control group and an unknown number of ALS patients were excluded. The rate ratio and 95% confidence interval (CI) were used for association measures in case-control and cohort studies. After full-text and abstract review, data from 8 studies with a total of 547,622 participants and 13,890 cases of ALS were entered in the present meta-analysis. We combined eight studies using a random-effect model and the RR for statin users among groups was 0.98 (95% CI 0.80-1.20) which indicates no association between statin and incidence of ALS. Also high heterogeneity was detected across the studies (Q value = 26.62, P = .00; I2 = 72.71%). In our meta-analysis study, we found no association between statin use and an increase in ALS incidence. This result is in line with some previous studies and provides strong evidence that denies the possible association between statin uptake and disease induction.
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Affiliation(s)
- Fardin Nabizadeh
- Neuroscience Research Group (NRG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad Balabandian
- Neuroscience Research Group (NRG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Amir Mohammad Sharafi
- Student's Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Ghaderi
- Student's Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Rostami
- Neuroscience Research Group (NRG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Abdorreza Naser Moghadasi
- Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
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