Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, China.
Neurotherapeutics. 2019 Oct;16(4):1097-1105. doi: 10.1007/s13311-019-00762-z.
Spinocerebellar ataxia type 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP), which functions as a general transcription factor. Like other polyQ expansion-mediated diseases, SCA17 is characterized by late-onset and selective neurodegeneration, despite the disease protein being ubiquitously expressed in the body. To date, the pathogenesis of polyQ diseases is not fully understood, and there are no effective treatments for these devastating disorders. The well-characterized function of TBP and typical neurodegeneration in SCA17 give us opportunities to understand how polyQ expansion causes selective neurodegeneration and to develop effective therapeutics. In this review, we discuss the molecular mechanisms behind SCA17, focusing on transcriptional dysregulation as its major cause. Mounting evidence suggests that reversing transcriptional alterations induced by mutant TBP and reducing the expression of mutant TBP are promising strategies to treat SCA17.
脊髓小脑共济失调 17 型（SCA17）是由 TATA 框结合蛋白（TBP）中的多聚谷氨酰胺（polyQ）扩展引起的，TBP 作为一种通用转录因子发挥作用。与其他多聚 Q 扩展介导的疾病一样，SCA17 的特征是发病晚且选择性神经退行性变，尽管疾病蛋白在体内广泛表达。迄今为止，多聚 Q 疾病的发病机制尚未完全阐明，这些破坏性疾病也没有有效的治疗方法。TBP 的特征功能和 SCA17 中的典型神经退行性变为我们提供了机会来了解多聚 Q 扩展如何导致选择性神经退行性变，并开发有效的治疗方法。在这篇综述中，我们讨论了 SCA17 的分子机制，重点讨论了其主要原因转录失调。越来越多的证据表明，逆转突变 TBP 诱导的转录改变和降低突变 TBP 的表达是治疗 SCA17 的有前途的策略。
