遗传性共济失调(Hereditary ataxia , HA)是一大类具有高度临床和遗传异质性、致死和致残率高的神经退行性疾病。前期工作中，我们应用全基因外显子组测序结合全基因组拷贝数变异分析，在一个常染色体隐性遗传性共济失调家系中克隆出致病基因UBA5。UBA5属于类泛素活化酶家族成员，参与类泛素分子Ufm1的活化。研究表明UBA5介导Ufm1类泛素化修饰通路在调控细胞的增殖过程和保护内质网应激诱导的细胞凋亡中发挥重要作用。我们前期的研究结果发现突变导致UBA5的稳定性和功能活性显著降低。本研究拟在前期工作基础上探讨UBA5介导Ufm1类泛素化修饰在小脑颗粒细胞增殖和凋亡中的作用机制以及小脑UBA5表达缺失小鼠的行为学及病理变化，从而为阐明遗传性共济失调发病机制提供依据。

Hereditary ataxia (HA) is a group of clinical and genetic heterogeneous neurodegenerative disorders with high mortality and disability. In our previous work, we identified mutations in ubiquitin-like modifier activating enzyme 5 gene ( UBA5) in one Chinese pedigree presenting with autosomal recessive cerebellar ataxia. UBA5 is one of the ubiquitin-like activating enzyme family members, which is involved in the activation of ubiquitin-like modifier Ufm1. Recent studies have indicated that UBA5 mediating the Ufm1 modification pathway plays an important role in regulating cell proliferation and protecting the endoplasmic reticulum stress induced apoptosis. Our previous study demonstrated that UBA5 mutants had less stablility and reduced activity. We aim to further investigate the mechanism of UBA5 mediating the Ufm1 modification in the proliferation and apoptosis of cerebellar granule cells as well as the behavioral and pathological changes of the mice with UBA5 knockdown in cerebellum in order to provide some evidences for elucidating the pathogenesis of HA.