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基因突变导致帕金森综合征或进行性核上性麻痹(PSP)的额颞部痴呆的临床表型，尸检显示这两种疾病都以tau病理为主。MAPT基因座上的常见变异进一步定义了两种非重组MAPT单倍型(MAPT H1和H2)，这两种单倍型是由古老的倒位引起的。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都相关。目前尚不清楚MAPT基因的哪个变异导致了这种风险，以及疾病的潜在病理机制是什么。该项目致力于解决PD和PSP患者MAPT基因座内与疾病相关的遗传变异，表征其患病率和效应大小，并确定其功能后果。具体目标集中在1)通过使用DNA池策略对350个PD、350个PSP和350个对照进行下一代测序，识别MAPT基因组区域的遗传变异；2)在广泛的PD和PSP病例对照人群中分析MAPT常见和罕见变异的遗传关联；以及3)研究MAPT变异对MAPT体外转录、翻译和选择性剪接的影响。 人脑。这些研究有助于充分认识MAPT中常见和罕见的变异在帕金森病发病中的作用，并有助于更好地理解帕金森病和PSP中tau功能障碍的发病机制。

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.