Alpha-Synuclein Regulation by microRNAs

microRNA 调节 α-突触核蛋白

• 批准号: 8223288
• 负责人: Eunsung Junn
• 金额: $ 34.13万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 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/8223288
• 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; public health relevance; 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. PUBLIC HEALTH RELEVANCE: Parkinson's disease and related progressive disorders of the brain have abnormal accumulation of a protein called alpha-synuclein in brain cells. The amount of this protein is critical in promoting its accumulation, which is believed to be harmful to these cells. Therefore, learning what controls the amount of this protein will help devise new treatments of these diseases. This project will study a new mechanism that controls alpha-synuclein levels.

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。 公共卫生相关性：帕金森氏病和相关的脑部疾病在脑细胞中称为α-核蛋白的蛋白质异常积累。该蛋白质的量对于促进其积累至关重要，这被认为对这些细胞有害。因此，学习控制该蛋白质量的是什么将有助于设计这些疾病的新疗法。该项目将研究一种控制α-核蛋白水平的新机制。