亨廷顿病是最主要的遗传性神经退行性疾病之一，主要由具有过长谷氨酰胺重复的变异HTT蛋白的毒性引起。目前与其他类似疾病一样，缺乏治疗手段。申请人近5年的前期工作利用遗传学筛选系统揭示了变异HTT蛋白水平的调控基因（相关通讯作者论文发表于Nature Neuroscience、Nature Chemical Biology、Cell Research等）。其中，纹状体富集的Gpr52可显著调控变异HTT蛋白水平并影响疾病表型（发表于eLife 2015）。由于GPR52属于G蛋白偶联受体，具有较高制药潜力。本项目拟在与病人遗传学方面高度相似的基因敲入小鼠的亨廷顿病模型模型中，运用遗传学及化学生物学手段，研究GPR52被小分子拮抗剂在体抑制或利用腺相关病毒在体敲减是否降低降低疾病蛋白水平并拯救在体神经退行及相关功能表型。本项目的实施将揭示亨廷顿病根本性治疗的新药靶及可能的小分子药物。

Huntington’s disease (HD) is an important disease among the neurodegenerative disorders and proteinopathies because of its monogenetic nature.HD is an autosomal dominant monogenetic disorder caused by an expanded CAG repeat in exon 1 of the HTT gene, resulting in the expression of an mutant HTT protein (mHTT) with a polyglutamine repeat containing greater than ~36Q. Although wild-type HTT (wtHTT) may have some neuroprotective functions, the gain of toxic function of mHTT, rather than loss of activity of wtHTT, is the major cause of the disease. ..In our previous work in the past five years, the applicant’s lab has carried out a number of screening efforts and identified a number of genetic modifiers of the mHTT protein level, and the applicant has published a number of research papers as the corresponding author in Nature Neuroscience, Nature Chemical Biology, eLife, Cell Research, etc. Among the modifiers that we have identified, Gpr52 is of special interest, because it is a G protein-coupled receptor (GPCR) that is highly druggable. ..In this study, we will test the potential effect of targeting Gpr52 on HTT levels and HD relevant phenotypes. In addition, we will investigate the molecular mechanism of Gpr52-mediated HTT regulation. The results will provide critical evidence for validating Gpr52 as a drug target for HD as well as novel insights into disease mechanisms, providing conceptual advances for targeted drug discovery of monogenetic neurodegenerative disorders.