Genetic Analysis of alpha-Synuceinopathies

本建议用于α-突触核病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一系列帕金森症 障碍，包括帕金森氏症，帕金森症和痴呆症，路易斯痴呆症 小体和多系统萎缩；α-突触核蛋白无疑是 散发性和家族性疾病。 我们的目标是：1)识别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 鉴定SNCA倍增突变；3)定量检测正常人群SNCA基因表达 衰老和疾病，以及；4)从功能上评估基因及其基因的遗传变异性 推动者。此外，我们将研究α-突触核蛋白的转录结果。 SNCA患者的人脑组织在模型系统中的过度表达 乘法。 我们的目标是提供有意义的分子诊断来重新分类这种异质性 将疾病分组，分成不同的组，进行进一步的纵向和病理评估。

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.