Understanding the role of MAPT in Parkinsonian disorders

描述（由申请人提供）： 编码微管相关蛋白tau的MAPT基因内的突变导致额颞叶痴呆伴帕金森综合征或进行性核上性麻痹（PSP）的临床表型，两者在尸检时均显示主要的tau病理学。MAPT基因座的常见变体进一步定义了由古老倒位产生的两种非重组MAPT单倍型（MAPT H1和H2）。最近的全基因组关联研究表明，MAPT H1是帕金森病（PD）和PSP的重要危险因素;然而，初步的亚单倍型分析表明，MAPT H1单倍型上的不同遗传变异与这些帕金森病中的每一种相关。目前还不清楚MAPT基因座的哪种变异导致了这种风险，以及疾病的潜在病理机制是什么。该项目旨在解决PD和PSP患者MAPT基因座内的疾病相关遗传变异，以表征患病率和效应量，并确定功能后果。具体目标集中在1）通过使用DNA汇集策略对350例PD、350例PSP和350例对照进行下一代测序，鉴定MAPT基因组区域中的遗传变异; 2）在广泛的PD和PSP病例对照人群中对MAPT中常见和罕见变异进行遗传关联分析; 3）MAPT变异体对MAPT转录、翻译和可变剪接的影响的体外和体内研究 人脑拟议的研究与充分了解MAPT中常见和罕见变异对帕金森病发展的贡献有关，并将有助于更好地了解PD和PSP中与tau功能障碍相关的疾病机制。 公共卫生相关性： 项目叙述本提案旨在确定MAPT中常见和罕见变异对两种最常见帕金森病（PD和PSP）发展的全部贡献。拟议的研究将有助于我们通过改善患者诊断、开发新病因疾病模型的能力以及增加对MAPT相关病理机制的理解来理解和治疗帕金森综合征患者的能力，这可能最终为可能的治疗策略提供信息。

DESCRIPTION (provided by applicant): Mutations within the MAPT gene encoding the microtubule-associated protein tau result in the clinical phenotype of frontotemporal dementia with parkinsonism or progressive supranuclear palsy (PSP) both displaying predominant tau pathology at autopsy. Common variants at the MAPT locus further define two non- recombining MAPT haplotypes (MAPT H1 and H2) resulting from an ancient inversion. Recent genome-wide association studies have implicated MAPT H1 as a significant risk factor for both Parkinson's disease (PD) and PSP; however preliminary sub-haplotype analyses suggest that different genetic variants on the MAPT H1 haplotype associate with each of these parkinsonian disorders. It currently remains unclear which variation at the MAPT locus is responsible for the risk and what is the underlying pathomechanism of disease. This project sets out to resolve the disease-associated genetic variation within the MAPT locus for both PD and PSP patients, to characterize the prevalence and effect size and to determine the functional consequence. The Specific Aims are focused on 1) identification of genetic variants in the MAPT genomic region through next-generation sequencing of 350 PD, 350 PSP and 350 controls using a DNA pooling strategy; 2) genetic association analyses of common and rare variants in MAPT in extensive PD and PSP case-control populations; and 3) study of the effect of MAPT variants on MAPT transcription, translation and alternative splicing in vitro and in human brain. The proposed studies are relevant to fully appreciate the contribution of common and rare variants in MAPT to the development of parkinsonian disorders and will contribute to a better understanding of the disease mechanism associated with tau dysfunction in PD and PSP. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This proposal is designed to determine the full contribution of common and rare variants in MAPT to the development of the two most common parkinsonian disorders, PD and PSP. The proposed studies will contribute to our understanding of and our ability to treat patients with parkinsonism through improved patient diagnosis, the ability to develop novel etiologic disease models and an increased understanding of the MAPT associated pathomechanism(s), which may ultimately inform possible therapeutic strategies.