钙转运蛋白ATP2B1在HD和SCA17等多聚谷氨酰胺疾病中的作用及机制研究

亨廷顿病（HD）和脊髓小脑共济失调17型（SCA17）是两类累及纹状体的多聚谷氨酰胺（polyQ）疾病，有关这两种退行性疾病纹状体病变的分子机制仍有待进一步研究。前期转录组学分析发现编码质膜钙转运蛋白的ATP2B1基因的转录水平在两种疾病小鼠模型纹状体中都显著下调。进一步敲除ATP2B1基因发现，纹状体中型多棘神经元丢失，胞内钙离子水平显著增加。因此我们推测，突变亨廷顿蛋白（HTT）和TATA盒结合蛋白（TBP）通过下调ATP2B1基因转录引起胞内钙稳态失衡，诱发细胞死亡导致HD和SCA17的纹状体退行性病变。为了验证这一假说，本项目拟进一步研究突变HTT和TBP蛋白影响ATP2B1转录的具体机制，以及ATP2B1降低引起钙稳态失衡导致纹状体病变的分子机理。本项目的完成对阐明HD和SCA17这两类polyQ疾病的病理机制具有重要意义，也为该类疾病的治疗提供理论支撑。

Huntington’s disease (HD) and spinocerebellar ataxia type 17 (SCA17) are two types of polyglutamine diseases with striatum lesions. The molecular mechanisms of striatal degeneration in these two degenerative diseases remain to be further studied. Previous transcriptome analysis revealed that the transcription level of ATP2B1 gene encoding plasma membrane calcium transporter was significantly down-regulated in the striatum of mouse models of both diseases. Furthermore, knocking out the ATP2B1 gene led to loss of medium spiny neurons and significantly increased intracellular calcium ion levels. Therefore, we hypothesize that mutant huntingtin protein (HTT) and TATA box binding protein (TBP) induce intracellular calcium dyshomeostasis by down-regulating ATP2B1 gene transcription, which causes cell death and leads to striatal degeneration of HD and SCA17. In order to verify this hypothesis, this project intends to further elucidate the specific mechanism of how mutant HTT and TBP proteins affect ATP2B1 transcription, as well as the molecular mechanism of how ATP2B1 reduction causes calcium dyshomeostasis and striatal degeneration. The completion of this project is of great significance to elucidate the pathological mechanism of polyQ diseases and to provide theoretical support for the treatment of these diseases.