Genetic Analysis of alpha-Synuceinopathies

α-突触神经氨酸病的遗传分析

• 批准号: 6842191
• 负责人: MATTHEW J FARRER
• 金额: $ 25.6万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842191
• 关键词: DNA footprinting; Lewy body; Parkinson' s disease; aging; alpha synuclein; dementia; disease /disorder classification; family genetics; gel mobility shift assay; gene expression; gene mutation; genetic polymorphism; genetic promoter element; genotype; haploidy; human population genetics; human subject; linkage mapping; luciferin monooxygenase; molecular genetics; molecular pathology; natural gene amplification; neural degeneration; neurogenetics; patient oriented research; phenotype; syndrome

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.

该提案用于 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一系列帕金森病 疾病，包括帕金森病、帕金森病和痴呆、路易痴呆 身体和多系统萎缩； α-突触核蛋白无疑是其核心成分 散发性和家族性疾病。 我们的目标是：1) 识别 SNCA 基因座的遗传变异并确定什么 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) 量化正常细胞中 SNCA 基因的表达 衰老和疾病，以及； 4）从功能上评估基因及其内部的遗传变异性 发起人。此外，我们要检查 α-突触核蛋白的转录结果 在模型系统中，在 SNCA 病例的人脑组织中过度表达 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 将疾病组分成不同的组，以进行进一步的纵向和病理评估。 由于 α-突触核蛋白的半衰期较长（约 30 小时），因此我们的工作重点是表征 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强有力的治疗策略来预防α-突触核蛋白病或阻止其进展。