Generation and Characterization of Novel Drosophila Models of TDP-43 Toxicity

描述（由申请方提供）：额颞叶变性（FTLD）是一种与额叶和/或颞叶局灶性萎缩相关的进行性神经退行性疾病。近年来的研究进展表明，FTLD和肌萎缩侧索硬化症（ALS）有共同的发病机制。例如，TDP-43是一种进化上保守的RNA结合蛋白，主要定位于细胞核，是涉及FTLD和ALS以及其他神经退行性疾病的主要致病蛋白。然而，关于TDP-43如何促进年龄依赖性神经退行性变知之甚少。TDP-43促进RNA代谢的几个方面，疾病的发生或进展可能涉及TDP-43正常功能的丧失和毒性功能获得机制。为了详细剖析这些复杂的机制，适当的体内动物模型至关重要。我们建议建立新的果蝇模型TDP-43的毒性和研究疾病突变如何妥协TDP-43的功能，并导致体内神经元功能障碍。这些研究将可能为涉及TDP- 43病理学的几种神经退行性疾病的分子致病机制提供重要见解。 公共卫生相关性：在这个计划中，我们将建立一个新的神经退行性变的果蝇模型，并进行一些遗传和分子实验。这些研究将为突变TDP-43的神经毒性提供新的机制见解，这可能会增强我们对额颞叶痴呆和肌萎缩侧索硬化症分子致病机制的理解。

DESCRIPTION (provided by applicant): Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes. Recent exciting progress indicates that FTLD and amyotrophic lateral sclerosis (ALS) share pathogenic mechanisms. For instance, TDP-43, an evolutionarily conserved RNA- binding protein mostly localized to the nucleus, is a major pathogenic protein involved in FTLD and ALS, and in other neurodegenerative diseases. However, little is known about how TDP-43 contributes to age-dependent neurodegeneration. TDP-43 contributes to several aspects of RNA metabolism, and disease initiation or progression may involve both loss of the normal function of TDP-43 and toxic gain-of-function mechanisms. To dissect these complex mechanisms in detail, proper in vivo animal models are critically important. We propose to establish novel Drosophila models of TDP-43 toxicity and investigate how disease mutations compromise the function of TDP-43 and lead to neuronal dysfunction in vivo. These studies will likely provide important insights into the molecular pathogenic mechanisms of several neurodegenerative diseases that involve TDP- 43 pathology. PUBLIC HEALTH RELEVANCE: In this proposal, we will establish a novel fly model of neurodegeneration and perform a number of genetic and molecular experiments. These studies will offer novel mechanistic insights into the neurotoxicity of mutant TDP-43, which will likely enhance our understanding of molecular pathogenic mechanisms of frontotemporal dementia and amyotrophic lateral sclerosis.