脊髓小脑性共济失调35（SCA35）致病基因TGM6的转基因小鼠功能研究

TGM6是我们前期工作中克隆的脊髓小脑性共济失调35亚型（SCA35）致病基因。TGM6编码蛋白TG6是转谷氨酰胺酶（TG）家族成员之一，TGs主要催化谷氨酰胺残基的咪唑羧酰胺基团与赖氨酸残基的ε氨基基团反应，参与了SCA、阿尔兹海默病、帕金森病及亨廷顿病等多种神经退行性疾病的发病过程，但其具体发病机制仍不明确。本课题拟在前期工作的基础上，构建野生型和突变型TGM6转基因小鼠，观察其行为学变化，了解内源性TG6蛋白在中枢神经系统的分布及表达TG6神经元的性质，观察转基因小鼠外源性TG6蛋白的分布和表达变化及神经病理学改变。从行为学、组织化学和病理生理学等多角度在生物整体水平探讨TGM6突变在SCA发病机制中的作用，为SCA发病机制研究和药物研发提供有价值的动物模型，为今后此类疾病的诊断、预防和治疗提供理论依据。

In our previous study we have cloned TGM6, a new causative gene of autosomal dominant spinocerebellar ataxia type 35. Transglutaminase 6 protein is a member of the transglutaminase family whose most common function is to catalyze the formation of isopeptide linkages between the carboxamide group of protein bound glutamine residues and the ε-amino group of protein-bound lysine residue. TGs may contribute to the pathogenesis of many neurodegenerative disorders, including spinocerebellar ataxia，Alzheimer's disease, Parkinson's disease， and Huntington's disease, but the details of its mechanism is not clear. In this study, we intend to establish wild and mutant TGM6 transgenic mouse models to explore the distribution of endogenous TG6 and the characters of neurons that express it in normal controls, and to observe the distribution and pathogenesis alternatins of exogenous TG6 in transgentic models. Besides, we explore the role that TGM6 mutation plays in SCA from the overall level of experimental animals in several aspects，including ethology, histochemistry and pathophysiology. Our study can provide practical SCA models for future researches and theoretical clues for diagnosis, prevention and therapy of SCA.