Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching.
BACKGROUND
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.


RESULTS
Here we demonstrate that overexpression of Drosophila TDP-43 (dTDP-43) in vivo significantly increases dendritic branching of sensory neurons in Drosophila 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 Drosophila neurons, and this function was attenuated by mutations associated with ALS.


CONCLUSIONS
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.
Lu
Yubing
Y
Gladstone Institute of Neurological Disease, and Department of Neurology, University of California, San Francisco, CA 94158, USA. ylu@gladstone.ucsf.edu
Ferris
Jacob
J
Gao
Fen-Biao
FB
D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology; D004331:Drosophila melanogaster / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D011984:Sensory Receptor Cells / Q000378:metabolism; D016019:Survival Analysis
D004268:DNA-Binding Proteins