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

突触核蛋白转录变体在神经元病理学和功能中的作用

• 批准号: 8685360
• 负责人: Asa Abeliovich
• 金额: $ 34.65万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685360
• 关键词: 3' Untranslated Regions; Biological Models; Brain; Brain Pathology; Complex; Corpus striatum structure; Data; Disease; Dopamine; Drug Targeting; Elements; Generations; Genetic; Genetic Polymorphism; Goals; Human; Inherited; Lead; Levodopa; Lewy Bodies; Mediating; Messenger RNA; Midbrain structure; Mitochondria; Modeling; Molecular; Molecular Target; Mutation; Neurons; Parkinson Disease; Pathogenesis; Pathology; Physiological; Play; Population; Preclinical Drug Evaluation; Presynaptic Terminals; Process; Property; Protein Isoforms; Proteins; Publishing; Rattus; Regulation; Reporting; Rodent; Role; Single Nucleotide Polymorphism; Site; Structure; Substantia nigra structure; Synaptic Transmission; Therapeutic; Transcript; Translations; Untranslated Regions; Variant; Virus; alpha synuclein; alpha synuclein gene; base; disorder risk; dopaminergic neuron; genetic variant; genome wide association study; in vivo; interest; neuron loss; neuronal survival; new therapeutic target; novel; novel therapeutic intervention; public health relevance; risk variant; synuclein; synuclein, alpha (non A4 component of amyloid precursor) protein, human; synucleinopathy; therapeutic target

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.

描述（由申请人提供）：人群中常见的遗传变异在非家族性（“散发性”）帕金森病（PD）的发病机制中发挥着重要作用。在此类 PD 风险变异中，α-突触核蛋白 (aSyn) 位点特别令人感兴趣，因为该位点中的 SNP 对散发性 PD 风险显示出最强且最稳健的影响。此外，aSyn 中非常罕见的突变以及 aSyn 基因的三倍体位点导致 PD 的家族遗传形式。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。我们的初步数据指出了一种新的调节机制，我们假设该机制会影响 aSyn 的生理和病理功能：aSyn 信使 RNA (mRNA) 转录物差异 3' 非翻译区 (3'UTR) 使用。在人脑和模型系统中，较长的转录亚型 (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。这最终可能通过专门针对 aSyn 的病理功能而非生理功能来提供一种新的治疗方法。 aSyn 3'UTR 的使用会因多巴胺暴露以及 aSyn 位点常见遗传单核苷酸多态性 (SNP) 变异而改变，这些变异会增加 PD 风险。这两种机制看起来很大程度上是独立的。虽然 3'UTR 的一小段（足以赋予多巴胺敏感性）在啮齿动物 aSyn 中是保守的，但大多数 3'UTR 序列是人类独有的。我们的具体假设是，人类 aSyn 的较长 mRNA 转录亚型（具有延长的 3'UTR）aSynL 通过影响 aSyn 蛋白的积累而发挥重要的病理作用。该提案的目标是 (i) 定义 aSyn 3'UTR 的调节机制，以及 (ii) 将不同 aSyn mRNA 3'UTR 亚型的分子特性与体内病理性 aSyn 功能联系起来。该提议的影响可能很大，因为精确定位特定的致病转录本将提出一个新的治疗靶点。这种监管可能特别适合高含量药物筛选。该项目的可交付成果是 (i) 提供 aSyn 3'UTR 序列与 aSyn 调节相关的结构/功能分析，以及 (ii) 通过确定介导的分子机制，潜在地确定 PD 和其他突触核蛋白病的新药物靶点的过程。