Interactions between TDP-43 and microRNA-92 in Drosophila and human neurons

描述（由申请方提供）：额颞叶痴呆（FTD）是一种主要的老年前期年龄依赖性痴呆，其特征为几种临床特征，包括进行性行为变化和语言障碍。TDP-43是FTD中的主要病理蛋白，其在病变神经元中从细胞核易位至细胞质，表明TDP-43核功能丧失可能是关键致病机制。包括我们自己在内的几项研究表明，microRNA（miRNA）通路中的缺陷是TDP-43下游的重要分子改变之一。以果蝇为模型，我们发现microRNA-92 a/B在果蝇TDP-43（dTDP-43）功能缺失突变体中显著下调。为了进一步了解miRNA在机制水平上的功能，我们产生了microRNA-92 a和microRNA-92 b单突变和双突变果蝇品系。在这个R21应用中，我们提出了分子，细胞，遗传分析，以进一步研究这种神经系统富集和进化保守，但未充分研究的miRNA家族功能的TDP-43下游调节突触和树突状结构在果蝇和人类神经元。这些研究可能为可能导致FTD和相关神经退行性疾病早期疾病表型的复杂分子调控机制提供新的见解。

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a major presenile age-dependent dementia characterized by several clinical features including progressive behavioral changes and language impairments. TDP-43 is a major pathological protein in FTD whose translocation from the nucleus to the cytoplasm in diseased neurons suggests loss of TDP-43 nuclear function may be a key pathogenic mechanism. Several studies including our own implicate defects in the microRNA (miRNA) pathway are one of the important molecular alterations downstream of TDP-43. Using Drosophila as a model, we found that microRNA-92a/b are significantly downregulated in Drosophila TDP-43 (dTDP-43) loss of function mutants. To further understand miRNA functions at the mechanistic level, we generated microRNA-92a, and microRNA-92b single and double mutant fly lines. In this R21 application, we propose molecular, cellular, genetic analyses to further investigate how this nervous system-enriched and evolutionarily conserved but understudied miRNA family functions downstream of TDP-43 to regulate synaptic and dendritic structures in Drosophila and human neurons. These studies will likely provide novel insights into the complex molecular regulatory mechanisms that may contribute to early disease phenotypes in FTD and related neurodegenerative disorders.