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.
In this proposal, we will perform a number of experiments to examine the functions of microRNAs in dendritic and synaptic formation and the functional significance of TDP-43-microRNA interactions in frontotemporal dementia. These studies will offer novel mechanistic insights into microRNA functions and disease mechanisms.