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.

该建议是用于α-核疾病中SNCA的分子遗传评估。我们的数据 表明α-核蛋白的过表达足以引起帕金森氏症 疾病，包括帕金森氏病，帕金森氏症和痴呆，痴呆 身体和多系统萎缩； α-突触核蛋白无疑是 零星和家族疾病。 我们的目的是：1）确定SNCA基因座的遗传变异性并确定什么 它对这些表型的贡献； 2）分子，临床和病理 表征SNCA繁殖突变； 3）量化正常的SNCA基因表达 衰老和疾病，以及； 4）在功能上评估基因及其内部的遗传变异性 发起人。此外，我们将检查α-突触核蛋白的转录后果 过表达，在模型系统中，在人类脑组织中的SNCA病例 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 一组疾病，分为不同的群体，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），因此我们的工作专注于表征SNCA遗传变异性，转录调控和mRNA表达。我们认为α-突触核蛋白表达的降低可能会提供强大的治疗策略，以防止α-突触核酸或停止其进展。