Molecular and Genetic Dissection of TDP-43 Function in Neurodegeneration

描述（由申请人提供）：TDP-43是肌萎缩侧索硬化（ALS）和某些形式的额颞叶痴呆（FTD）中的主要病理蛋白，也存在于其他神经退行性疾病中的泛素化包涵体中。TDP-43如何促进年龄依赖性神经退行性变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，其在有丝分裂后神经元中的功能尚未得到广泛研究。通常，TDP-3具有弥散的核分布。然而，在患病的神经元中，TDP-43及其加工片段聚集成细胞质泛素化内含物。因此，TDP-43正常功能的丧失可能导致神经退行性变，可能与其他机制相一致，例如TDP-43片段的毒性功能获得。在这个R21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：在本申请中，我们将检验以下假设：TDP-43活性的丧失影响神经元结构完整性，因此导致与许多年龄依赖性神经退行性疾病相关的最终神经退行性疾病。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.