Alpha-Synuclein Regulation by microRNAs

microRNA 调节 α-突触核蛋白

• 批准号: 8704606
• 负责人: Eunsung Junn
• 金额: $ 32.64万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704606
• 关键词: 3' Untranslated Regions; Address; Affect; Age of Onset; Alleles; Animal Model; Animals; Autopsy; Base Sequence; Behavior; Behavioral; Binding; Brain; Brain Diseases; Brain region; Cell model; Cells; Computer software; Disease; Disease Progression; Disease model; Down-Regulation; Functional RNA; Functional disorder; Gene Dosage; Gene Expression; Gene Targeting; Genes; Goals; Human; Individual; Inherited; Investigation; Knock-out; Knowledge; Lasers; Learning; Lewy Bodies; Libraries; Link; Mediating; Messenger RNA; MicroRNAs; Microdissection; Molecular and Cellular Biology; Motor; Mus; Names; Nerve Degeneration; Neurites; Neurons; Outcome; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Proteins; Publications; Regulation; Research; Rodent; Role; SNCA gene; Sampling; Substantia nigra structure; System; Testing; Toxic effect; Transcript; Transgenes; Transgenic Animals; Transgenic Organisms; Viral Vector; alpha synuclein; base; brain cell; dopaminergic neuron; in vivo; inhibitor/antagonist; mouse model; novel therapeutic intervention; oxidation; protein aggregation; research study; synuclein; synucleinopathy; therapeutic target; transgene expression; vector control

DESCRIPTION (provided by applicant): a-Synuclein (a-Syn) is a key protein in the pathogenesis of Parkinson's disease (PD) and other a- synucleinopathies. Postmortem investigations have demonstrated fibrillar a-Syn aggregates in Lewy bodies and Lewy neurites in affected brain regions in these disorders. A critical factor in the pathologic aggregation of this protein appears to be its intraneuronal concentration. Besides the fact that multiplication of the a-Syn gene locus is linked to dominantly inherited PD with an onset age that correlates inversely with gene dosage, transgenic animal models expressing wild-type human a-Syn manifest phenotypic changes reminiscent of this disease, and various cellular models in culture are made vulnerable to oxidative insults by over-expressing this protein. All these observations collectively indicate that over-expression of a-Syn is deleterious to neurons and particularly to nigral dopaminergic neurons. microRNA (miRNA) is a small (19- 24 nt) endogenous non-coding RNA which binds to the 3'-untranslational region (UTR) of mRNA in a sequence-specific manner, thereby suppressing expression of target genes. Recently, we found that miRNA-7 (miR-7) represses a-Syn protein level by targeting the 3'-UTR of this transcript. Further, miR-7- induced down-regulation of a-Syn protects cells against oxidative stress in cellular models. This application proposes to investigate the function of miRNAs including miR-7 in the pathogenesis of PD in relation to a- Syn regulation. We hypothesize that certain miRNAs repress a-Syn expression in vivo and that dysfunction of specific miRNA species results in loss of this check mechanism in disease states, leading to increased a- Syn expression and ultimately neurodegeneration. Both cellular and mouse models will be employed to carry out these investigations. Since inhibitors of a-Syn expression are attractive therapeutic targets for PD and other a-synucleinopathies, detailed understanding of these mechanisms provides potential new therapeutic approaches to slow or halt PD progression.

描述（由申请人提供）：A-突触核蛋白（A-SYN）是帕金森氏病（PD）和其他A-突触核酸的发病机理中的关键蛋白质。验尸研究表明，在这些疾病中，在受影响的大脑区域中路易体和路易神经突的原纤维A-syn聚集体。该蛋白质的病理聚集的关键因素似乎是其神经元浓度。除了以下事实：A-Syn基因基因座的繁殖与主要遗传的PD相关，其发作年龄与基因剂量相反，表达野生型人类A-syn表现表型的转基因动物相反，使这种疾病的表现为这种疾病，并且在培养物中具有多种细胞模型，可以使这种源具有氧化的蛋白质。所有这些观察结果共同表明，A-Syn的过表达对神经元，尤其是对nigral多巴胺能神经元有害。 microRNA（miRNA）是一种小（19-24 nt）内源性非编码RNA，以序列特异性方式与mRNA的3'-非翻译区（UTR）结合，从而抑制靶基因的表达。最近，我们发现miRNA-7（miR-7）通过靶向该转录本的3'-UTR来抑制A-Syn蛋白水平。此外，miR-7诱导的A-SYN下调可保护细胞免受细胞模型中的氧化应激。该应用建议研究与A-Syn调控有关的miRNA在PD发病机理中的功能。我们假设某些miRNA在体内抑制A-Syn的表达，并且特定miRNA物种的功能障碍导致疾病状态下这种检查机制的丧失，从而导致A- SYN表达增加并最终导致神经变性。细胞模型和小鼠模型均应采用这些研究。由于A-SYN表达的抑制剂是PD和其他A-突触核病的有吸引力的治疗靶标，因此对这些机制的详细理解为缓慢或停止PD进展提供了潜在的新治疗方法。