Molecular and Genetic Dissection of TDP-43 Function in Neurodegeneration

描述(申请人提供)：TDP-43是肌萎缩侧索硬化症(ALS)和某些形式的额颞部痴呆(FTD)的主要病理蛋白，也存在于其他神经退行性疾病中的泛素化包涵体中。TDP-43在年龄依赖性神经退行性变中的作用在很大程度上是未知的。TDP-43是一种进化上高度保守的RNA结合蛋白，主要定位于细胞核，参与转录抑制、选择性剪接、mRNA运输以及可能的RNA代谢的其他方面。然而，它在有丝分裂后神经元中的功能还没有得到广泛的研究。正常情况下，TDP-3呈弥漫性核分布。然而，在患病的神经元中，TDP-43及其处理过的碎片聚集成细胞质泛素化的包涵体。因此，TDP-43正常功能的丧失可能导致神经变性，可能与其他机制相一致，例如TDP-43片段的毒性功能获得。在R21的应用中，我们建议研究内源性TDP-43在有丝分裂后神经元中的正常功能，这将可能为TDP-43相关神经变性的分子机制提供重要的见解。 公共卫生相关性：在这项应用中，我们将测试TDP-43活性丢失影响神经元结构完整性从而导致最终与一些年龄相关的神经退行性疾病相关的神经退行性变的假设。为此，我们将使用果蝇作为我们所有拟议研究的主要模型系统。

DESCRIPTION (provided by applicant): TDP-43 is a major pathological protein in amyotrophic lateral sclerosis (ALS) and some forms of frontotemporal dementia (FTD) and is also present in ubiquitinated inclusions seen in other neurodegenerative diseases. How TDP-43 contributes to age-dependent neurodegeneration is largely unknown. TDP-43, an evolutionarily highly conserved RNA-binding protein mostly localized to the nucleus, participates in transcriptional repression, alternative splicing, mRNA trafficking, and possibly other aspects of RNA metabolism. However, its functions in postmitotic neurons have not been extensively studied. Normally, TDP-3 has a diffuse nuclear distribution. In diseased neurons, however, TDP-43 and its processed fragments aggregate into cytoplasmic ubiquitinated inclusions. Thus, loss of the normal function ofTDP-43 might contribute to neurodegeneration, perhaps in concert with other mechanisms, such as a toxic gain-of-function for TDP-43 fragments. In this R21 application, we propose to investigate the normal functions of endogenous TDP-43 in postmitotic neurons, which will likely provide important insight into the molecular mechanisms underlying TDP-43-related neurodegeneration. PUBLIC HEALTH RELEVANCE: In this application, we will test the hypothesis that loss of TDP-43 activity affects neuronal structural integrity therefore contributes to eventual neurodegeneration associated with a number of age-dependent neurodegenerative diseases. To this end, we will use fruitfly Drosophila as our primary model system for all the proposed studies.