PIAS1 S510G variant acts as a genetic modifier of spinocerebellar ataxia type 3 by selectively impairing mutant ataxin-3 proteostasis.

Autor: Chang YC; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Tsai YC; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Chang EC; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Hsu YC; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Huang YR; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Lee YH; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 11529, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan., Tsai YS; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Chen YQ; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Lee YC; Department of Neurology, Taipei Veterans General Hospital, Taipei 11221, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Liao YC; Department of Neurology, Taipei Veterans General Hospital, Taipei 11221, Taiwan., Kuo JC; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Su MT; School of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan., Yang UC; Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan., Chern Y; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 11529, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan., Cheng TH; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. Electronic address: thcheng@nycu.edu.tw.
Jazyk: angličtina
Zdroj: The international journal of biochemistry & cell biology [Int J Biochem Cell Biol] 2024 Nov; Vol. 176, pp. 106662. Date of Electronic Publication: 2024 Sep 16.
DOI: 10.1016/j.biocel.2024.106662
Abstrakt: Dysregulated protein homeostasis, characterized by abnormal protein accumulation and aggregation, is a key contributor to the progression of neurodegenerative disorders such as Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Previous studies have identified PIAS1 gene variants in patients with late-onset SCA3 and Huntington's disease. This study aims to elucidate the role of PIAS1 and its S510G variant in modulating the pathogenic mechanisms of SCA3. Through in vitro biochemical analyses and in vivo assays, we demonstrate that PIAS1 stabilizes both wild-type and mutant ataxin-3 (ATXN3). The PIAS1 S510G variant, however, selectively reduces the stability and SUMOylation of mutant ATXN3, thereby decreasing its aggregation and toxicity while maintaining the stability of wild-type ATXN3. This effect is mediated by a weakened interaction with the SUMO-conjugating enzyme UBC9 in the presence of mutant ATXN3. In Drosophila models, downregulation of dPIAS1 resulted in reduced levels of mutant ATXN3 and alleviated associated phenotypes, including retinal degeneration and motor dysfunction. Our findings suggest that the PIAS1 S510G variant acts as a genetic modifier of SCA3, highlighting the potential of targeting SUMOylation as a therapeutic strategy for this disease.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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