突变ataxin-3蛋白选择性侵犯脊髓小脑性共济失调3型患者不同脑区神经元的病理机制

脊髓小脑性共济失调3型(SCA3)是我国最常见的SCA亚型，常在青壮年发病，因发病机制不清迄今无药可医，致残率及自杀率非常高，阐明其发病机制并寻找治疗靶点一直是本病的研究热点和重点。申请人前期对SCA3的临床表型与基因型关系进行了系列研究，发现SCA3的高度临床异质性与突变ataxin-3蛋白选择性侵犯不同脑区神经元密切相关，这可能是SCA3发病的重要环节，但病理机制不清。基于此，我们建立了细菌人工染色体(BAC)-SCA3转基因小鼠，本项目将利用Cre-LoxP重组酶系统进一步建立分别在大脑、小脑和中脑选择性敲除异常扩增CAG重复序列的条件性基因敲除小鼠，构建携带不同CAG重复片段的人源iPS细胞并定向诱导分化为各种神经元，分别从在体和离体途经，阐明突变ataxin-3蛋白选择性侵犯SCA3患者不同脑区神经元的病理机制，这有助于进一步阐明SCA3的发病机制，并为寻找治疗靶点提供理论依据。

Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA in China, which often occurs in young and middle-aged people. Because of the unclear pathogenesis, there is no medicine available so far, and the rate of disability and suicide is very high, so it is always the research hotspot and focus to clarify its pathogenesis and find the treatment target. The applicant has conducted a series of studies on the relationship between the clinical phenotype and genotype of SCA3. It is found that the clinical heterogeneity of SCA3 is closely related to the selective invasion of neurons in different brain areas by the mutant ataxin-3 protein, which may be an important link for the pathogenesis of SCA3, but the pathological mechanism remains unclear. Based on this, we have established bacterial artificial chromosome (BAC)-SCA3 transgenic mice. In this project, Cre-LoxP recombinase system will be used to further establish conditional knockout mice with abnormal amplification of CAG repeat sequence knocked out in brain, cerebellum and midbrain, respectively. Human iPS cells carrying different CAG repeat segments will be constructed and differentiated into various neurons. In vitro and in vivo approaches will be used to elucidate the pathological mechanism of mutant ataxin-3 protein selectively invading neurons in different brain regions of patients with SCA3, which is helpful to further elucidate the pathogenesis of SCA3 and provide theoretical basis for finding therapeutic targets.