Deactivation of TBP contributes to SCA17 pathogenesis

Tun Chieh Hsu, Cheng Kuang Wang, Chun Yen Yang, Li Ching Lee, Hsiu Mei Hsieh-Li, Long Sun Ro, Chiung Mei Chen, Guey Jen Lee-Chen, Ming Tsan Su

研究成果: 雜誌貢獻期刊論文同行評審

14 引文 斯高帕斯(Scopus)

摘要

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by the expansion of polyglutamine (polyQ) within the TATA box-binding protein (TBP). Previous studies have shown that polyQ-expanded TBP forms neurotoxic aggregates and alters downstream genes. However, how expanded polyQ tracts affect the function of TBP and the link between dysfunctional TBP and SCA17 is not clearly understood. In this study, we generated novel Drosophila models for SCA17 that recapitulate pathological features such as aggregate formation, mobility defects and premature death. In addition to forming neurotoxic aggregates, we determined that polyQ-expanded TBP reduces its own intrinsic DNA-binding and transcription abilities. Dysfunctional TBP also disrupts normal TBP function. Furthermore, heterozygous dTbp amorph mutant flies exhibited SCA17-like phenotypes and flies expressing polyQ-expanded TBP exhibited enhanced retinal degeneration, suggesting that loss of TBP function may contribute to SCA17 pathogenesis. We further determined that the downregulation of TBP activity enhances retinal degeneration in SCA3 and Huntington's disease fly models, indicating that the deactivation of TBP is likely to play a common role in polyQ-induced neurodegeneration.

原文英語
頁(從 - 到)6878-6893
頁數16
期刊Human molecular genetics
23
發行號25
DOIs
出版狀態已發佈 - 2014 十二月 20

ASJC Scopus subject areas

  • 分子生物學
  • 遺傳學
  • 遺傳學(臨床)

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