Molecular neuropathology of TDP-43 proteinopathies

项目摘要 肌萎缩侧索硬化症（ALS）和额颞叶变性（FTD）是两个相关的 神经退行性疾病共享重叠的临床、病理和遗传特征。ALS-FTD 一系列疾病都是致命的，既无治疗方法，也无治愈方法。有显著 病理学和遗传学数据的融合表明，RNA代谢异常与 ALS和FTD中的神经变性。本提案的总体目标是定义分子神经病理学 ALS和FTD的研究了解与特定的 脑病理学将揭示ALS/FTD的分子发病机制。新方法是 其中病理蛋白质或神经元是从人脑中分离出来的，用于深入的分子分析。 提出了两个具体的目标，这将（1）确定病理性TDP-43的分子组成， 蛋白质内含物，和（2）确定由于正常核TDP的丢失而导致的RNA加工异常， 43蛋白质。这些研究将通过使用高度创新的方法， 用先进的分子技术研究人脑组织。

Project Summary Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are two related neurodegenerative diseases which share overlapping clinical, pathologic and genetic features. The ALS-FTD spectrum of diseases is uniformly fatal, and there is neither treatment nor cure. There is a remarkable convergence of pathologic and genetic data which indicate that abnormal RNA metabolism is linked to neurodegeneration in ALS and FTD. The overall goal of this proposal is define the molecular neuropathology of ALS and FTD using human brain tissue. Understanding the molecular aberrations associated with specific brain pathologies will reveal insights into the molecular pathogenesis of ALS/FTD. Novel methods are presented in which pathologic proteins or neurons are isolated from human brain for deep molecular analysis. Two specific aims are proposed which will (1) determine the molecular composition of pathologic TDP-43 protein inclusions, and (2) identify the abnormalities in RNA processing due to the loss of normal nuclear TDP- 43 protein. These studies will further our understanding of TDP-43 proteinopathies by using highly innovative techniques to study human brain tissue with advanced molecular techniques.