| Summary: | <p>Abstract</p> <p>Background</p> <p>TDP-43 is an evolutionarily conserved RNA-binding protein implicated in the pathogenesis of frontotemporal dementia (FTD), sporadic and familial amyotrophic lateral sclerosis (ALS), and possibly other neurodegenerative diseases. In diseased neurons, TDP-43 is depleted in the nucleus, suggesting a loss-of-function pathogenic mechanism. However, the normal function of TDP-43 in postmitotic neurons is largely unknown.</p> <p>Results</p> <p>Here we demonstrate that overexpression of <it>Drosophila </it>TDP-43 (dTDP-43) in vivo significantly increases dendritic branching of sensory neurons in <it>Drosophila </it>larvae. Loss of dTDP-43 function, either in a genetic null mutant or through RNAi knockdown, decreased dendritic branching. Further genetic analysis demonstrated a cell-autonomous role for dTDP-43 in dendrite formation. Moreover, human TDP-43 (hTDP-43) promoted dendritic branching in <it>Drosophila </it>neurons, and this function was attenuated by mutations associated with ALS.</p> <p>Conclusion</p> <p>These findings reveal an essential role for TDP-43 in dendritic structural integrity, supporting the notion that loss of normal TDP-43 function in diseased neurons may compromise neuronal connectivity before neuronal cell loss in FTD and ALS.</p>
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