title: Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells.
abstract: Spinocerebellar ataxia-3 (SCA3) is the most common dominant inherited ataxia worldwide and is caused by an unstable CAG trinucleotide expansion mutation within theATXN3gene, resulting in an expanded polyglutamine tract within the ATXN3 protein. Manyin vitrostudies 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 SCA3in vitrousing 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< 0.05). In conclusion, patient-derived iPS cells are a good model for studying the mechanisms of SCA3 and may provide a tool for drug discoveryin vitro.
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Zhanhui
authors.initials: Z
authors.lastname: Ou
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Niu
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Wenyin
authors.initials: W
authors.lastname: He
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Song
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Yexing
authors.initials: Y
authors.lastname: Xian
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Di
authors.initials: D
authors.lastname: Fan
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Shuming
authors.initials: S
authors.lastname: OuYang
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Xiaofang
authors.identifier: 0000-0002-3308-5325
authors.initials: X
authors.lastname: Sun
mesh_terms: D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D059785:Karyotype; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3