亨廷顿病(HD)由亨廷顿蛋白(Htt)基因突变所致，HD患者和转基因动物脑内有明显的突触功能障碍，突变Htt通过对基因转录的异常调控影响多种突触蛋白的表达与突触传递障碍有关。突触小泡蛋白2(SV2)是一类对突触传递具有调节作用的糖蛋白，其C亚型SV2C选择性表达于基底神经节等HD病变脑区。我们在HD转基因小鼠纹状体等脑区发现SV2C基因转录明显降低；生物信息学分析显示，阻遏子元件沉默转录因子(REST)可能是SV2C基因的转录抑制因子，可能通过SV2C基因启动子上与阻遏子元件1(RE1)序列相似的RE1样序列互作调控SV2C表达；我们的初步实验也显示，改变REST表达水平可改变SV2C的转录表达。本项目将在证明REST是SV2C基因的转录抑制因子基础上，分析REST和RE1样序列在突变Htt抑制SV2C表达的分子机制，为揭示突变Htt损害突触传递功能的机制和发现治疗HD的新靶点提供依据。

Huntington's disease (HD) is a neurodegenerative disorder caused by mutation of the gene for huntingtin (Htt). There is defect in neuronal transmission in the brains of HD patients and transgenic mouse models. Mutant Htt could affect the expression of a series of synaptic proteins through gene dysregulation, causing dysfunction of synaptic transmission. Synaptic protein 2 (SV2) is a class of glycoprotein involved in regulation of synaptic transmission, isoform C of which is selectively expressed in the HD pathology-selective regions, such as basal ganglia. Our preliminary work has found that transcription of SV2C gene is downregulated in the striatum of HD transgenic mouse brains. Bioinformatic analysis has showed that repressor element silencing transcription factor (REST) could be an inhibitory transcription factor of SV2C gene. It is likely that REST regulates expression of SV2C viainteracting with a sequence in the promoter of SV2C gene, which is similar to the sequence of repressor element 1(RE1). Our preliminary data also showed that the alteration of REST expression caused the change in transcription of SV2C gene. In the present project, we will firstly try to demonstrate that REST is an inhibitory transcription factor of SV2C gene, and then analyze the role of REST and RE1-like sequence in mutant Htt inhibiting transcription of SV2C gene, probing for the underlying molecular mechanism of mutant Htt inhibiting SV2C expression via REST. Hopefully, the project could provide new evidence for revealing the mechanism of synaptic transmission impairment by mutant Htt and for finding new target of treating HD.