Gene discovery in PSP by transcriptome, neuropathology and sequence analysis

描述（由申请人提供）：进行性核上性麻痹（PSP）是一种快速进展的神经退行性疾病，具有临床病理异质性，没有任何治疗。遗传学研究可以帮助鉴定PSP风险及其异质性的分子病理生理学，从而发现治疗靶点。直到最近，编码tau的MAPT的H1单倍型是PSP最强的遗传危险因素。一项新的PSP全基因组关联研究（GWAS）确定了6个额外的位点。将这些发现有效地转化为治疗需要识别疾病基因、功能变异及其作用机制。这些目标不能仅靠GWAS疾病来实现，需要其他的、强有力的和机械的方法。目前的建议旨在通过联合分析全转录组和定量神经病理学测量，在一个具有现有GWAS数据的具有良好特征的尸检PSP队列中缩小这一知识差距。我们的长期目标是揭示PSP的病理生理学和其亚型的分子底物，最终导致药物的发现。鉴于PSP和其他牛头病变之间的临床病理重叠，我们的建议有望影响广泛的神经退行性疾病，并产生新的治疗途径。我们的中心假设是，许多PSP变异通过调节大脑基因表达而赋予风险。此外，不同的转录调控可能是PSP异质性的基础。我们的初步数据确定了一些顶级PSP GWAS变体的脑转录关联，支持我们的假设。在我们的脑库中，我们从已有GWAS的尸检PSP受试者中获得了近500个脑样本，其中约400个具有典型临床病理，约100个具有非典型临床病理。所有受试者都有临床数据和详细的定量神经病理学测量。我们的目标是在这个独特的队列中获得脑转录组测量值，并将其与定量神经病理学测量相结合进行分析，以确定PSP风险的功能变异，其临床病理异质性，并发现这些变异的作用机制。我们的具体目标的预期结果是：1)确定a)影响PSP大脑中基因表达的遗传变异，b) PSP亚型之间转录水平的差异，这不仅仅是由于衰老造成的；2)发现a)影响PSP神经病理和基因表达的遗传因素；B)与神经病理学相关的转录本；3)通过对200个PSP脑样本进行下一代RNA测序，揭示PSP的转录调控机制；B)体外翻译研究。所有目标的结果将与PSP疾病GWAS进行比较。整体的知识将提名基因及其转录变化作为PSP的新疾病机制。这些分子机制将构成可改变的药物靶点，影响PSP和其他相关的神经退行性疾病。

DESCRIPTION (provided by applicant): Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder with clinicopathologic heterogeneity and without any therapies. Genetic studies can be instrumental in the identification of the molecular pathophysiology underlying PSP risk and its heterogeneity, which may enable discovery of therapeutic targets. Until recently, H1 haplotype of MAPT, encoding tau, was the strongest genetic risk factor for PSP. A new PSP genome-wide association study (GWAS) identified six additional loci. The effective translation of these findings to therapy requires identification of he disease gene, the functional variants and their mechanism of action. These goals cannot be achieved by the disease GWAS alone and require alternative, powerful and mechanistic approaches. The current proposal aims to close this knowledge gap by joint analysis of the whole transcriptome and quantitative neuropathology measures in a well- characterized autopsied PSP cohort with existing GWAS data. Our long-term goal is to uncover the pathophysiology of PSP and the molecular substrates of its subtypes that will ultimately lead to drug discoveries. Given the clinicopathological overlap between PSP and other tauopathies, our proposal is expected to impact a wide range of neurodegenerative disorders and generate novel therapeutic avenues. Our central hypothesis, is that many PSP variants confer risk by regulating brain gene expression. Further, differential transcriptional regulation may underlie the heterogeneity in PSP. Our preliminary data identified brain transcript associations for some of the top PSP GWAS variants supporting our hypothesis. In our Brain Bank, we have access to nearly 500 brain samples from autopsied PSP subjects with existing GWAS, ~400 of which have typical and ~100 with atypical clinicopathology. All subjects have clinical data and detailed quantitative neuropathology measures. Our objective is to obtain brain transcriptome measurements in this unique cohort, which will be analyzed jointly with quantitative neuropathology measures to identify functional variants underlying PSP risk, its clinicopathological heterogeneity and to discover the mechanism of action of these variants. The expected outcomes of our specific aims are: 1) To identify a) genetic variants that influence gene expression in PSP brains, b) transcript level differences between subtypes of PSP that are not simply due to aging; 2) To discover a) genetic factors that influence both neuropathology and gene expression in PSP; b) transcripts that correlate with neuropathology; 3) To uncover the mechanism of transcriptional regulation in PSP by a) next-generation RNA sequencing of 200 select PSP brain samples; b) translational in- vitro studies. Results from all aims will be compared with the PSP disease GWAS. The overall knowledge will nominate genes and their transcriptional changes as novel disease mechanisms in PSP. These molecular mechanisms will constitute modifiable drug targets, which will impact PSP and other related neurodegenerative diseases.