Genetic Analysis of alpha-Synuceinopathies

该建议是用于α-突触核蛋白病中SNCA的分子遗传学评估。我们的数据 显示α-突触核蛋白过度表达足以引起帕金森综合征 疾病，包括帕金森病、帕金森综合征和痴呆、路易氏痴呆 体和多系统萎缩; α-突触核蛋白无疑是一个中心组成部分， 散发性和家族性疾病。 我们的目标是：1）确定SNCA基因座的遗传变异性，并确定 它对这些表型的贡献; 2）分子，临床和病理学 表征SNCA倍增突变; 3）定量正常人中SNCA基因表达， 衰老和疾病，以及; 4）功能性评估基因内的遗传变异及其 启动子此外，我们将研究α-突触核蛋白的转录后果 在模型系统中，在来自SNCA病例的人脑组织中过表达 乘法 我们的目标是提供有意义的分子诊断，以重新分类这种异质性 将一组疾病分成不同的组，以进行进一步的纵向和病理评估。 由于α-突触核蛋白具有延长的半衰期（约30小时），因此我们的工作集中于表征SNCA遗传变异性、转录调控和mRNA表达。我们认为α-突触核蛋白表达的减少可能提供一种有效的治疗策略来预防α-突触核蛋白病或阻止其进展。

This proposal is for molecular genetic assessment of SNCA in alpha-synucleinopathy. Our data shows alpha-synuclein overexpression is sufficient to give rise to a spectrum of Parkinsonism disorders, including Parkinson's disease, parkinsonism and dementia, dementia with Lewy bodies and multiple system atrophy; alpha-synuclein is undoubtedly a central component in sporadic and familial disease. Our aims are to: 1) identify genetic variability in the SNCA locus and determine what contribution it has to these phenotypes; 2) molecularly, clinically and pathologically characterize SNCA multiplication mutations;, 3) quantify SNCA gene expression in normal aging and disease, and; 4) functionally assess genetic variability within the gene and its promoter. Furthermore, we are to examine the transcriptional consequence of alpha-synuclein over-expression, in model systems, in human brain tissue from cases with SNCA multiplication. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases, into distinct groups, for further longitudinal and pathological assessment. As alpha-synuclein has an extended half-life (approximately 30hrs), thus our work is focused on characterizing SNCA genetic variability, transcriptional regulation and mRNA expression. We posit reduction in alpha-synuclein expression may provide a powerful therapeutic strategy to prevent alpha-synucleinopathy or halt its progression.