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四疾病中的Tau H1关联，包括进行性核上核PALSY（PSP）和皮质性肥胖变性（CBD），对其病因至关重要，但基本的突变和对Tau生物学的功能效应仍然是神秘的。帕金森氏病（PD）存在类似的tau H1关联，这一点显然是一种非常不同的疾病，这是非常引人注目的。然而，tau是PD病例的嗅球和杏仁核中α-核蛋白/路易病理学的一致特征，并且PSP患者的一部分患有Lewy尸体。动物模型还质疑缠结在神经毒性中的经典定义作用。 我们的初步数据采用了相对孤立的挪威中部人口，明确表明：l）tau h1变体与帕金森氏病有关； 2）tau h1是一个错误的名称，是单倍型的覆盖物，并且； 3）该样品中的遗传分析足以确定负责的功能突变。我们的应用具有三个目的：1）Tau H1的高分辨率遗传分析，包括评估连锁不平衡，单倍型甲板和与临床疾病的关联； 2）从同质性挪威分离株中复制和扩展发现到更异质的美国样本，包括PD病例/对照组，以及病理确认的突触核苷病和tauopathy，以及； 3）TAU单倍型和定义它们的变体的基因组和功能分析。 提出的工作中的遗传见解将对疾病疾病，诊断测试和患者治疗产生重大影响。如前所述，我们将克隆与疾病相关的变体，并使更广泛的研究社区可用来开发体内模型，其中疾病病因可能会进一步揭示并开发出治疗。