Genetic Analysis of Tau H1 in Parkinsonism

帕金森病 Tau H1 的遗传分析

• 批准号: 6762800
• 负责人: MATTHEW J FARRER
• 金额: $ 35.63万
• 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: 2004-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6762800
• 关键词: Parkinson' s disease; clinical research; family genetics; fluorescent in situ hybridization; functional /structural genomics; gel mobility shift assay; genetic polymorphism; genetic susceptibility; genotype; histopathology; human genetic material tag; human population genetics; human subject; human tissue; linkage disequilibriums; linkage mapping; neurogenetics; postmortem; tau proteins

DESCRIPTION (provided by applicant): The tau H1 association in 4R tauopathies, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), is fundamental to their etiology, yet the underlying mutation(s) and functional effects on tau biology remain enigmatic. It is remarkable, though more controversial, that a similar tau H1 association exists for Parkinson's disease (PD), clearly a very different disorder. However, tau is a consistent feature of the alpha-synuclein/Lewy pathology in the olfactory bulb and amydala of PD cases and a subset of PSP patients have Lewy bodies present. Animal models have also questioned the classical defining role of tangles in neurotoxicity in tauopathies. Our Preliminary data, employing the relatively isolated population of central Norway, shows unequivocally that: l) tau H1 variants are associated with Parkinson's disease; 2) tau H1 is a misnomer and is a haplotype clad, and; 3) genetic analysis within this sample is sufficiently powerful to identify the functional mutation responsible. Our application has three Aims: 1) High-resolution genetic analysis of tau H1 including assessment of linkage disequilibrium, haplotype cladistics and association to clinical disease; 2) Replicating and extending findings from a homogeneous Norwegian isolate to more heterogeneous US samples, including a PD case/control cohort and pathologically confirmed synucleinopathy and tauopathy, and; 3) Genomic and functional analysis of tau haplotypes and the variants which define them. Genetic insights from the work proposed will have major ramifications for disease nosology, diagnostic testing and patient treatment. As previously, we would clone the disease-associated variants identified and make constructs available to the wider research community for the development of in-vivo models, in which the disease etiology may be further unraveled and treatments developed.

描述（由申请人提供）：4R tau蛋白病（包括进行性核上性麻痹（PSP）和皮质基底节变性（CBD））中的tau H1关联是其病因学的基础，但潜在的突变和对tau生物学的功能影响仍然是个谜。值得注意的是，尽管更具争议性，帕金森病 (PD) 也存在类似的 tau H1 关联，而帕金森病显然是一种截然不同的疾病。然而，tau 蛋白是 PD 病例嗅球和杏仁核中 α-突触核蛋白/路易体病理学的一致特征，并且部分 PSP 患者存在路易体。动物模型也对缠结在 tau蛋白病神经毒性中的经典定义作用提出了质疑。 我们的初步数据采用挪威中部相对孤立的人群，明确表明： l) tau H1 变异与帕金森病相关； 2) tau H1 是用词不当，是一种单倍型，并且； 3) 该样本中的遗传分析足以识别导致的功能突变。我们的应用有三个目标：1) tau H1 的高分辨率遗传分析，包括评估连锁不平衡、单倍型分支学和与临床疾病的关联； 2) 将挪威同质分离株的研究结果复制并扩展到更异质的美国样本，包括 PD 病例/对照队列和病理证实的突触核蛋白病和 tau 蛋白病，以及； 3) tau 单倍型及其定义变体的基因组和功能分析。 这项工作的遗传学见解将对疾病分类学、诊断测试和患者治疗产生重大影响。与以前一样，我们将克隆已识别的与疾病相关的变异，并将构建体提供给更广泛的研究界，以开发体内模型，在该模型中，可以进一步阐明疾病病因并开发治疗方法。