Alpha-Synuclein Regulation by microRNAs

microRNA 调节 α-突触核蛋白

基本信息

批准号：
8792636
负责人：
Eunsung Junn
金额：
$ 34.13万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792636
关键词：
3&apos 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 disorder Gene Dosage Gene Expression Gene Targeting Genes Goals Health 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 Untranslated RNA Viral Vector alpha synuclein base brain cell dopaminergic neuron in vivo inhibitor/antagonist mouse model novel therapeutic intervention oxidation protein aggregation research study synucleinopathy targeted sequencing therapeutic target transgene expression vector control

项目摘要

DESCRIPTION (provided by applicant): α-Synuclein (α-Syn) is a key protein in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. Postmortem investigations have demonstrated fibrillar α-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 α-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 α-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 α-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 α-Syn protein level by targeting the 3'-UTR of this transcript. Further, miR-7- induced down-regulation of α-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 α-Syn regulation. We hypothesize that certain miRNAs repress α-Syn expression in vivo and that dysfunction of specific miRNA species results in loss of this check mechanism in disease states, leading to increased α-Syn expression and ultimately neurodegeneration. Both cellular and mouse models will be employed to carry out these investigations. Since inhibitors of α-Syn expression are attractive therapeutic targets for PD and other α-synucleinopathies, detailed understanding of these mechanisms provides potential new therapeutic approaches to slow or halt PD progression.

描述（由应用提供）：α-突触核蛋白（α-Syn）是帕金森氏病（PD）和其他α-突触核苷的发病机理中的关键蛋白质。验尸研究表明，这些疾病中受影响的大脑区域的路易体身体中的纤维α-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：α-syn基因基因座的繁殖与主要遗传的PD相关，其开始年龄与基因剂量相反，表达野生型人α-同步的转基因动物显然表现出表型的表型变化，使这种疾病的表现变化使各种细胞模型与培养中的各种细胞模型相关，使这种概况变得易于氧化，从而使这种概念过于氧化的氧化无关。所有这些观察结果共同表明，α-Syn的过表达被删除为神经元，尤其是对nigral多巴胺能神经元。 microRNA（miRNA）是一个小的（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反映了α-SYN蛋白水平。此外，miR-7诱导的α-Syn下调可保护细胞免受细胞模型中的氧化应激。该应用提出的提案是研究miRNA在PD发病机理中与α-Syn调控有关的功能。我们假设某些miRNA在体内抑制α-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α-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α-Syn表达的抑制剂是PD和其他α-Syn病路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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transglutaminase 2 Depletion Attenuates α-Synuclein Mediated Toxicity in Mice.

DOI：
10.1016/j.neuroscience.2020.05.047
发表时间：
2020-08-10
期刊：
Neuroscience
影响因子：
3.3
作者：
Zhang J;Grosso Jasutkar H;Yan R;Woo JM;Lee KW;Im JY;Junn E;Iismaa SE;Mouradian MM
通讯作者：
Mouradian MM

Inhibition of miR-34b and miR-34c enhances α-synuclein expression in Parkinson's disease.