Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the / gene. The expanded CAG repeats encode a polyglutamine (polyQ) tract at the C-terminus of the ATXN3 protein. ATXN3 containing expanded polyQ forms aggregates, leading to subsequent cellular dysfunctions including an impaired ubiquitin-proteasome system (UPS). To investigate the pathogenesis of SCA3 and develop potential therapeutic strategies, we established induced pluripotent stem cell (iPSC) lines from SCA3 patients (SCA3-iPSC). Neurons derived from SCA3-iPSCs formed aggregates that are positive to the polyQ marker 1C2. Treatment with the proteasome inhibitor, MG132, on SCA3-iPSC-derived neurons downregulated proteasome activity, increased production of radical oxygen species (ROS), and upregulated the cleaved caspase 3 level and caspase 3 activity. This increased susceptibility to the proteasome inhibitor can be rescued by a Chinese herbal medicine (CHM) extract NH037 (from ) and its constituent daidzein via upregulating proteasome activity and reducing protein ubiquitination, oxidative stress, cleaved caspase 3 level, and caspase 3 activity. Our results successfully recapitulate the key phenotypes of the neurons derived from SCA3 patients, as well as indicate the potential of NH037 and daidzein in the treatment for SCA3 patients.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800904 | PMC |
| http://dx.doi.org/10.1155/2019/8130481 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
White matter functional and structural alterations of spinocerebellar ataxia type 3: A longitudinal MRI study.
Neuroscience
December 2024
Department of Radiology, Xiangya Hospital of Central South University, Changsha, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital of Central South University, Changsha, 410008, China; Hunan Engineering Research Center for Intelligent Medical Imaging, Changsha, 410078, Hunan, China; FuRong Laboratory, Changsha, 410078, Hunan, China. Electronic address:
Widespread white matter (WM) microstructural abnormalities have been reported in patients with spinocerebellar ataxia type 3 (SCA3) using diffusion tensor imaging (DTI), whereas the ability of DTI to detect WM degeneration over short-term period remains insufficiently explored. Additionally, WM dysfunction remains entirely unknown in this disease. This study aims to investigate WM structural and functional alterations in SCA3, and provide promising progression biomarkers for short-term clinical trials.
View Article and Find Full Text PDFApolipoprotein E epsilon4 allele is associated with better performance language and visual memory in spinocerebellar ataxia type 3.
Eur J Neurol
January 2025
School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Background: The regulatory role of the apolipoprotein E (APOE) ε4 allele in the clinical manifestations of spinocerebellar ataxia type 3 (SCA3) remains unclear. This study aimed to evaluate the impact of the APOE ε4 allele on cognitive and motor functions in SCA3 patients.
Methods: This study included 281 unrelated SCA3 patients and 182 controls.
Gray Matter Asymmetry Alterations in Patients With Spinocerebellar Ataxia Type 3: A Voxel-Based Morphometric Comparison Study.
CNS Neurosci Ther
December 2024
7T Magnetic Resonance Imaging Translational Medical Center, Department of Radiology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Aims: The aim of this study was to investigate the whole-brain asymmetry changes in spinocerebellar ataxia type 3 (SCA3) and their association with movement disorders.
Methods: Voxel-based morphometry (VBM) was used to assess asymmetry in gray matter (GM) volume in 83 genetically confirmed SCA3 patients and 83 sex- and age-matched healthy controls (HCs). The asymmetry index (AI) was analyzed for partial correlation with disease severity, as measured by the Scale for Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS).
Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China.
Mov Disord
December 2024
Department of Neurology, Xiangya Hospital, Central South University, Changsha, P. R. China.
Background: Recent studies have reported that expanded GCA repeats in the GLS gene can cause glutaminase deficiency with ataxia phenotype. However, to data, no studies have investigated the distribution and role of GCA repeats in the GLS gene of Chinese individuals.
Objective: The aim was to investigate the distribution of GCA repeats in Chinese individuals, including undiagnosed ataxia patients for identifying causal factors, healthy controls for determining the normal range, and ATX-ATXN3 (spinocerebellar ataxia type 3, SCA3) patients for exploring genetic modifiers.
Tract-specific spinal damage in SCA2, SCA3 and SCA6.
J Neurol
December 2024
Faculdade de Ciências Médicas da UNICAMP, Departamento de Neurologia da FCM/UNICAMP, Department of Neurology, Universidade Estadual de Campinas, University of Campinas, Cidade Universitária s/n Caixa Postal, 6111 Barão Geraldo, 13083970, Campinas, SP, Brasil.
Background: Spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders characterized by progressive ataxia. Although previous studies have focused on cerebral and cerebellar damage, spinal cord involvement in SCAs remains underexplored.
Objectives: This study aims to characterize spinal cord abnormalities in SCA2, SCA3, and SCA6 and to identify its phenotypic correlates.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!