Molecular neuropathology of TDP-43 proteinopathies

项目摘要 肌萎缩侧索硬化症(ALS)和额颞部退行性变(FTD)是两个相关的疾病 具有重叠的临床、病理和遗传特征的神经退行性疾病。ALS-FTD 各种疾病都是致命的，既没有治疗方法，也没有治愈方法。有一个不同寻常的 病理和遗传数据的汇聚，表明RNA代谢异常与 肌萎缩侧索硬化症和FTD的神经变性。这项提议的总体目标是定义分子神经病理学 利用人脑组织进行肌萎缩侧索硬化症和功能性肌萎缩症的研究。了解与特定基因相关的分子像差 脑病理学将揭示ALS/FTD的分子发病机制。新的方法是 从人脑中分离出病理蛋白质或神经元以进行深入分子分析的方法。 提出了两个具体目标：(1)确定病理性TDP-43的分子组成 蛋白质包涵体，以及(2)确定由于正常核TDP-丢失而导致的RNA加工异常。 43蛋白质。这些研究将进一步加深我们对TDP-43蛋白病变的理解，使用高度创新的 用先进的分子技术研究人脑组织的技术。

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.