Genetic Analysis of Tau H1 in Parkinsonism

描述(由申请人提供)：tau H1与4R tau病，包括进行性核上性瘫痪(PSP)和皮质基底膜变性(CBD)有关，是其病因学的基础，但潜在的突变(S)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，但与帕金森氏病(PD)存在类似的tau H1关联，显然是一种非常不同的疾病。然而，tau是帕金森病患者嗅球和杏仁核中α-突触核蛋白/路易体病理的一致特征，部分PSP患者存在路易小体。动物模型也质疑缠结在紧张症神经毒性中的经典定义作用。 我们使用挪威中部相对与世隔绝的人群的初步数据明确地表明：L)tau H1变异与帕金森氏病有关；2)tau H1是一个错误的名称，是单倍型包裹；以及3)该样本中的基因分析足以确定导致相关的功能突变。我们的应用有三个目标：1)tau H1的高分辨率遗传分析，包括连锁不平衡、单倍型分支分析和与临床疾病的关联；2)复制和扩展来自同质挪威分离株的研究结果，并将其扩展到更多不同的美国样本，包括PD病例/对照队列以及经病理证实的联核症和互变病；以及3)tau单倍型和定义它们的变异的基因组和功能分析。 这项拟议工作的遗传学见解将对疾病病因学、诊断测试和患者治疗产生重大影响。像以前一样，我们将克隆已确定的与疾病相关的变异，并将构建结构提供给更广泛的研究社区，以开发体内模型，在体内模型中，疾病病因可能会进一步解开，治疗方法可能会被开发出来。

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.