ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism

作者：Rousseaux Maxime W C; Tschumperlin Tyler; Lu Hsiang Chih; Lackey Elizabeth P; Bondar Vitaliy V; Wan Ying Wooi; Tan Qiumin; Adamski Carolyn J; Friedrich Jillian; Twaroski Kirk; Chen Weili; Tolar Jakub; Henzler Christine; Sharma Ajay; Bajic Aleksandar; Lin Tao; Duvick Lisa; Liu Zhandong; Sillitoe Roy V; Zoghbi Huda Y^*; Orr Harry T^*

来源：Neuron, 2018, 97(6): 1235-+.

DOI：10.1016/j.neuron.2018.02.013

Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain-and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity.

• 出版日期2018-3-21