Project 1: Identifying genes and Pathways that impact Tau Toxicity in FTD

项目总结/摘要 进行性核上性麻痹（PSP）和皮质基底节变性（CBD）是帕金森病， 尸检时主要的tau病理学。一种常见的非重组单倍型在微管相关 染色体17q21上的tau蛋白基因（MAPT）位点增加了PSP和CBD的风险，最近我们发现， 全基因组关联的努力确定了其他基因/位点（STX6，EIF2AK3，SOS1，KIF13B， 和MOBP/Appoptosin）。此外，其他基因，尚未发现，可能有助于对PSP的易感性 CBD。本研究的目的是解决疾病相关的外显子组和整体遗传变异 PSP和CBD患者的基因组序列数据，以确定病理后果， 这些以tau病理为特征的复杂神经退行性疾病的潜在机制，因此 确定潜在的治疗靶点。对于目标1，我们将分析一个由600多个数据组成的独特数据集。 外显子组和2400个全基因组序列来自病理证实的PSP患者和350个外显子组 CBD患者这些数据将与通过阿尔茨海默氏症基因组获得的5000个对照外显子组进行比较。 用于单核苷酸变异（SNV）分析的测序项目。在目标2中，我们将扩展对此的分析 队列和具体分析结构变异（SV）和拷贝数变异（CNV），有助于 PSP和CBD使用一系列分析软件程序，我们已经广泛测试，以实现 对每种类型的变化的最佳灵敏度。对于目标3，我们将使用可用的外显子组和全基因组 序列数据，以评估tau毒性和病理学的遗传变异与核心C的关联， 评估不同脑区域中的tau负荷和作为神经元细胞损失的替代物的小神经胶质增生。正在进行 研究表明，使用定量病理学测量可以帮助区分PSP的亚型。为宗旨 4、我们将确定所鉴定的显著相关变异/基因的影响。我们将检测mRNA 表达，RNA-Seq数据，体外功能研究，以表征观察到的突变对tau蛋白的影响 聚集和微管组装，以及这些基因/变体对tau蛋白水平的影响， 在死后脑组织中发现的同种型总之，全外显子组和全基因组的结合 来自病理学证实和高表型患者的序列数据，并有深入的分析计划 重点关注SNV、CNV、SV和数量性状，为新基因发现提供了独特的机会。 鉴定tau蛋白病的新基因是更好地理解tau蛋白病的关键一步。 这组疾病的病理机制，并可能有助于确定这些预后的生物标志物 毁灭性的疾病

PROJECT SUMMARY/ABSTRACT Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are Parkinsonian disorders with predominant tau pathology at autopsy. A common non-recombining haplotype at the microtubule associated protein tau gene (MAPT) locus on chromosome 17q21 increases the risk of PSP and CBD and recently our genome-wide association efforts identified variation in additional genes/loci (STX6, EIF2AK3, SOS1, KIF13B, and MOBP/Appoptosin). In addition, other genes, as yet undetected, likely contribute to susceptibility to PSP and CBD. This study aims to resolve the disease-associated genetic variation within the exome and whole genome sequence data from PSP and CBD patients, to determine the pathological consequences and mechanisms underlying these complex neurodegenerative diseases characterized by tau pathology, thus identifying potential therapeutic targets. For Aim 1, we will analyze a unique dataset consisting of over 600 exomes and 2400 whole genome sequences derived from pathology-confirmed PSP patients and 350 exomes from CBD patients. These data will be compared to the 5000 control exomes available through the Alzheimer's sequencing project for single nucleotide variant (SNV) analysis. In Aim 2, we will expand our analysis of this cohort and specifically analyze structural variants (SV) and copy number variations (CNV) that contribute to PSP and CBD using a range of analytical software programs which we have extensively tested to achieve optimal sensitivity for each type of variation. For Aim 3, we will use the available exome and whole genome sequence data to assess the association of genetic variation on tau toxicity and pathology with Core C, by assessing tau burden in different brain regions and microgliosis as a surrogate of neuronal cell loss. On-going efforts have shown that using quantitative pathologic measures can help distinguish subtypes of PSP. For Aim 4, we will determine the effect of significantly associated variants/genes identified. We will examine mRNA expression, RNA-Seq data, in vitro functional studies to characterize the effect of the observed mutation on tau aggregation and microtubule assembly, and the effect of these genes/variants on tau protein levels and isoforms in postmortem brain tissue. In summary, the combination of whole exome and whole genome sequence data from pathologically-confirmed and highly-phenotyped patients with an in-depth analytical plan focusing on SNV, CNV, SV and quantitative traits, provides a unique opportunity for novel gene discovery. Identifying novel genes for tauopathies is a critical step towards a better understanding of the pathomechanisms underlying this group of disorders and may help identify prognostic biomarkers for these devastating disorders.