The role of a Synuclein transcript variants in neuronal pathology and function

描述(由申请人提供)：人类群体中常见的基因变异在非家族性(散发性)帕金森病(PD)的发病机制中发挥着重要作用。在这些PD风险变异中，α-突触核蛋白(ASyn)基因座尤其令人感兴趣，因为该基因座上的SNPs对散发性PD风险的影响最强和最强。此外，非常罕见的aSyn突变和aSyn基因座的三倍体导致家族性遗传性帕金森病。因此，aSyn是PD的一个有吸引力的治疗靶点，大多数策略旨在降低其水平或聚集性。我们的初步数据指出了一种新的调控机制，我们假设它会影响Syn的生理和病理功能：a Syn Messenger RNA(MRNA)转录差异3‘非翻译区(3’UTR)的使用。在人脑和模型系统中，较长的转录异构体(ASynL)与蛋白质积累增加、神经元内蛋白质重新分布和病理功能相关。这最终可能通过靶向aSyn的病理功能而不是生理功能来提供一种新的治疗方法。ASyn 3‘非编码区的使用被多巴胺暴露以及增加帕金森病风险的aSyn基因座常见的单核苷酸多态(SNP)变异所改变。这两种机制似乎在很大程度上是分开的。虽然啮齿动物aSyn中有一小部分3‘非编码区(足以赋予多巴胺敏感性)是保守的，但大多数3’非编码区序列是人类所独有的。我们的具体假设是，人类aSyn的较长的mRNA转录异构体，带有扩展的3‘UTRs，aSynL，通过影响aSyn蛋白的积累，发挥重要的病理作用。本研究的目的是：(1)明确aSyn 3‘非编码区的调控机制；(2)将不同的aSyn基因3’非编码区亚型的分子特性与体内aSyn的病理功能联系起来。这一提议的影响可能很高，因为精确定位特定的致病转录本将提供一个新的治疗靶点。这种监管可能尤其适用于含量较高的药物筛查。该项目的成果是(I)提供与Syn调控相关的a Syn 3‘UTR序列的结构/功能分析，以及(Ii)通过确定介导这一过程的分子机制，潜在地识别PD和其他联核病的新药物靶点。

DESCRIPTION (provided by applicant): Common genetic variants in the human population play a significant role in the pathogenesis of non-familial ('sporadic') Parkinson's disease (PD). Among such PD risk variants, the alpha-synuclein (aSyn) locus is of particular interest, as SNPs in this locus show the strongest and most robust impact on sporadic PD risk Furthermore, very rare mutations in aSyn as well as triplication of the aSyn gene locus lead to familial inherited forms of PD. aSyn is thus an attractive therapeutic target for PD, with most strategies aimed at reducing its level or aggregation. Our preliminary data point to a novel regulatory mechanism that we hypothesize to impact aSyn physiological and pathological functions: aSyn messenger RNA (mRNA) transcript differential 3' untranslated region (3'UTR) usage. Longer transcript isoforms (aSynL) correlate with increased protein accumulation, intraneuronal protein redistribution, and pathological functions, both in human brain and in model systems. This ultimately may provide a novel therapeutic approach by targeting specifically pathological rather than physiological functions of aSyn. aSyn 3'UTR usage is modified by dopamine exposure as well as by aSyn locus common genetic single nucleotide polymorphism (SNP) variants that increase PD risk. The 2 mechanisms appear largely separate. Whereas a small segment of the 3'UTR (sufficient to confer dopamine sensitivity) is conserved in rodent aSyn, most of the 3'UTR sequences are unique to human. Our specific hypothesis is that longer mRNA transcript isoforms of human aSyn, with extended 3'UTRs, aSynL, play important pathological roles, by impacting the accumulation of aSyn protein. The goals of this proposal are to (i) define regulatory mechanisms of the aSyn 3'UTR and (ii) relate the molecular properties of different aSyn mRNA 3'UTR isoforms to pathological aSyn functions in vivo. The impact of this proposal is potentially high, as pinpointing a specific pathogenic transcript would present a novel therapeutic target. Such regulation could be especially amenable to high-content drug screens. The deliverables of the project are (i) to provide a structure/function analysis of aSyn 3'UTR sequences with respect to aSyn regulation, and (ii) to potentially identify novel drug targets for PD and other synucleinopathies, by identifying molecular mechanisms that mediate the process.