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: 9045716
• 负责人: Asa Abeliovich
• 金额: $ 35万
• 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/9045716
• 关键词: 3' Untranslated Regions; Biological Models; Brain; Brain Pathology; Complex; Corpus striatum structure; Data; Disease; Dopamine; Elements; Generations; Genetic; Genetic Polymorphism; Goals; Health; 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; risk variant; 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）的发病机制中起重要作用。在这样的PD风险变体中，α-突触核蛋白（aSyn）基因座是特别感兴趣的，因为该基因座中的SNP显示出对散发性PD风险的最强和最稳健的影响。此外，aSyn中非常罕见的突变以及aSyn基因座的三重化导致家族遗传形式的PD。因此，aSyn是PD的有吸引力的治疗靶标，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控机制，我们假设该机制影响aSyn的生理和病理功能：aSyn信使RNA（mRNA）转录本差异3'非翻译区（3' UTR）使用。在人脑和模型系统中，较长的转录异构体（aSynL）与增加的蛋白质积累、神经元内蛋白质再分布和病理功能相关。这最终可以通过特异性靶向aSyn的病理功能而不是生理功能来提供新的治疗方法。aSyn 3 'UTR的使用被多巴胺暴露以及增加PD风险的aSyn基因座常见遗传单核苷酸多态性（SNP）变体修饰。这两种机制似乎在很大程度上是分开的。尽管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序列对人类是独特的。我们的具体假设是具有延伸的3 'UTR的人aSyn的较长mRNA转录物同种型aSyn L通过影响aSyn蛋白的积累而发挥重要的病理作用。该提议的目标是（i）定义aSyn 3 'UTR的调控机制和（ii）将不同aSyn mRNA 3' UTR同种型的分子特性与体内病理性aSyn功能相关联。这一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供一种新的治疗靶点。这种监管可能特别适用于高含量药物筛选。该项目的可交付成果是（i）提供aSyn 3 'UTR序列在aSyn调控方面的结构/功能分析，以及（ii）通过鉴定介导该过程的分子机制，潜在地鉴定PD和其他突触核蛋白病的新型药物靶标。