亨廷顿病是最主要的遗传性神经退行性疾病之一，主要由变异HTT蛋白的毒性引起。申请人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，论文发表于eLife、Nature Chemical Biology等期刊。课题组前期工作发现激酶基因MAPK11可以通过调控HTT的mRNA稳定性显著影响变异HTT蛋白水平，并影响疾病表型，但机制不明。申请人提出假说，认为MAPK11通过RNA结合蛋白影响了HTT的mRNA稳定性，并基于CLIP-seq数据库和初步筛选，发现RNA结合蛋白ELAVL1可能介导了MAPK11对HTT的调控。本项目拟运用遗传学及分子生物学手段，研究MAPK11通过ELAVL1调控HTT的机制，以及对疾病表型的潜在拯救作用。通过RNA结合蛋白调控HTT的mRNA稳定性以往未见任何报道，本项目的实施可能揭示HTT调控的全新机制，为疾病治疗提供新的切入点。

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 several genetic modifiers of the mHTT protein level, and the applicant has published a number of research papers in eLife, Nature Chemical Biology, etc. Among the modifiers that we have identified, MAPK11 is of special interest, because it is a kinase gene that is highly druggable. In addition, homozygous knock-out of Mapk11 does not seem to have any deleterious effect in mouse models, suggesting that inhibiting MAPK11 is safe. Meanwhile, the mechanism of MAPK11 mediated HTT regulation remains unclear, although our previous data demonstrated that MAPK11 regulates HTT by modulating its mRNA stability. .Thus, the applicant hypothesized that MAPK11 regulates HTT via RNA-binding protein(s) (RBPs), which may interacts with HTT mRNA and influence its stability. The applicant further tested a number of candidate RBPs based on published CLIP-seq data, and revealed ELAVL1 as the potential candidate RBP that mediates MAPK11’s effects on HTT..In this study, we will investigate the molecular mechanism of MAPK11-ELAVL1 mediated HTT regulation, and its potential pathological impacts. Regulations of HTT mRNA stability by RBPs have never been reported, and this project will reveal novel mechanisms of HTT regulation, providing new entry points to HD treatment.