Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells

Spinocerebellar ataxia-3 (SCA3) is the most common dominant inherited ataxia worldwide and is caused by an unstable CAG trinucleotide expansion mutation within the ATXN3 gene, resulting in an expanded polyglutamine tract within the ATXN3 protein. Many in vitro studies have examined the role of autop...

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Bibliographic Details
Published in:BioMed research international 2016-01, Vol.2016 (2016), p.1-11
Main Authors: OuYang, Shuming, Sun, Xiaofang, Fan, Di, Song, Bing, He, Wenyin, Xie, Yingjun, Chen, Yuchang, Niu, Xiaohua, Luo, Min, Ou, Zhanhui, Xian, Yexing
Format: Article
Language:English
Subjects:
Alzheimer's disease
Analysis
Ataxia
Ataxin-3 - genetics
Ataxin-3 - metabolism
Autophagy
Autophagy - genetics
Cell Differentiation - genetics
Cell division
Cell Line
Cytoplasm
Cytotoxicity
Dysphagia
Embryonic stem cells
Fibroblasts
Gene Expression Regulation
Genes
Genetic aspects
Homeostasis
Hospitals
Humans
Induced Pluripotent Stem Cells - metabolism
Induced Pluripotent Stem Cells - pathology
Karyotype
Laboratories
Machado-Joseph Disease - genetics
Machado-Joseph Disease - metabolism
Machado-Joseph Disease - pathology
Medical research
Medicine, Experimental
Mutation
Nervous system diseases
Neural Stem Cells - metabolism
Neural Stem Cells - pathology
Neurodegeneration
Neurons
Proteins
Proteolysis
Repressor Proteins - genetics
Repressor Proteins - metabolism
Science
Spinocerebellar ataxia
Stem cells
Studies
Trinucleotide Repeats - genetics
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Summary:Spinocerebellar ataxia-3 (SCA3) is the most common dominant inherited ataxia worldwide and is caused by an unstable CAG trinucleotide expansion mutation within the ATXN3 gene, resulting in an expanded polyglutamine tract within the ATXN3 protein. Many in vitro studies have examined the role of autophagy in neurodegenerative disorders, including SCA3, using transfection models with expression of pathogenic proteins in normal cells. In the current study, we aimed to develop an improved model for studying SCA3 in vitro using patient-derived cells. The patient-derived iPS cells presented a phenotype similar to that of human embryonic stem cells and could be differentiated into neurons. Additionally, these cells expressed abnormal ATXN3 protein without changes in the CAG repeat length during culture for at least 35 passages as iPS cells, up to 3 passages as neural stem cells, and after 4 weeks of neural differentiation. Furthermore, we demonstrated that neural differentiation in these iPS cells was accompanied by autophagy and that rapamycin promoted autophagy through degradation of mutant ATXN3 proteins in neurally differentiated spinocerebellar ataxia-3 human induced pluripotent stem cells (p
ISSN:2314-6133
2314-6141
DOI:10.1155/2016/6701793