ataxin-2蛋白通过结合ataxin-3突变蛋白入核并抑制转录因子REST的活性从而影响脊髓小脑性共济失调3型表型的机制研究

脊髓小脑性共济失调3型（spinocerebellar ataxia type 3，SCA3）发病机制不清，表型异质性高，且无有效治疗方案。申请者前期发现ATXN2基因的CAG重复序列影响SCA3发病年龄。进一步研究发现，ataxin-2蛋白polyQ区域通过与突变ataxin-3蛋白结合入核，在核内竞争性结合REST抑制其活性。据此，申请者提出假设：Ataxin-2的polyQ区域可介导其与ataxin-3突变蛋白结合，从而藉由ataxin-3携带入核，并通过竞争性结合REST使其失去转录抑制功能，进而修饰SCA3表型。本项目将应用SCA3转基因小鼠，构建细胞模型，明确ataxin-2在SCA3表型修饰中的作用，阐明ataxin-2异常核定位和REST异常活性的机制，探索干预ataxin-2或重激活REST缓解SCA3表型的潜在可能。这有助于揭示SCA3病理机制，为治疗提供新策略。

Spinocerebellar ataxia type 3 (SCA3) has an unclear pathogenesis, a high phenotypic heterogeneity and no effective treatment options. The pre-experiments observed that CAG repeat length of ATXN2 gene influences age at onset of SCA3. Further studies revealed that ataxin-2 protein is translocated into the nucleus through binding to mutant ataxin-3 protein depending on the polyQ region, and the ataxin2-ataxin3 complex competitively binds to the transcription factor REST and inhibits its activity. Accordingly, the applicant puts forward the hypothesis that the polyQ region of ataxin-2 could mediate its binding to mutant ataxin-3 protein, which then is carried into the nucleus by ataxin-3, and affects the repressive transcriptional function of REST by competitively binding to REST, thereby modifying the phenotype of SCA3. This project will use SCA3 transgenic mice model and establish cell model, to clarify the role of ataxin-2 in the modification of SCA3 phenotype through a series of in vitro and in vivo experiments, to elucidate the mechanism of aberrant nuclear localization of ataxin-2 and aberrant activity of REST, and to explore the potential of interfering with ataxin-2 or reactivating REST to alleviate the phenotype of SCA3. This will help reveal the pathological mechanism of SCA3 and provide new insights for SCA3 treatment.