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）：人口中的常见遗传变异在非家庭（“散发”）帕金森氏病（PD）的发病机理中起重要作用。在此类PD风险变异中，α-突触核蛋白（ASYN）基因座特别令人感兴趣，因为该基因座中的SNP显示出对零星PD风险的最强烈，最强大的影响，此外，Asyn中的突变非常罕见，Asyn Gene基因座的一倍次数也导致了家族性的pd形成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型的调节机制，我们假设它会影响ASYN生理和病理功能：Asyn Messenger RNA（mRNA）转录差3'未翻译区域（3'UTR）用法。在人脑和模型系统中，较长的转录本同工型（ASYNL）与蛋白质积累，神经元蛋白重新分布和病理功能的增加相关。最终，这可能通过针对ASYN的病理学而不是生理功能来提供一种新颖的治疗方法。 ASYN 3'UTR使用是通过多巴胺暴露以及ASYN基因座的常见遗传单核苷酸多态性（SNP）变体来修饰的，这些变体增加了PD风险。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）在啮齿动物的Asyn中是保守的，但大多数3'UTR序列都是人类独有的。我们的具体假设是，通过影响ASYN蛋白的积累，具有延长的3'UTR，Asynl的人类Asyn的mRNA转录本相结合型，扮演着重要的病理作用。该提议的目标是（i）定义ASYN 3'UTR的调节机制和（ii）将不同ASYN mRNA 3'UTR同工型的分子特性与体内的病理ASYN功能相关联。该提案的影响可能很高，因为指出特定的病原转录本将提出一个新的治疗靶标。这种调节可能尤其适合高含量药物屏幕。该项目的可交付成果是（i）通过鉴定介导该过程的分子机制，提供了ASYN 3'UTR序列的结构/功能分析，以及（ii）潜在地识别PD和其他促核核核酸的新型药物靶标。