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.
Gladstone Institute of Neurological Disease, and Department of Neurology, University of California, San Francisco, CA 94158, USA. ylu@gladstone.ucsf.edu
Yubing
Y
Lu
Jacob
J
Ferris
Fen-Biao
FB
Gao
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