Abstract
BackgroundTDP-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.ResultsHere 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.ConclusionThese 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.
Highlights
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
Because dendritic branching patterns are critically important for neuronal function and connectivity and dendritic defects are associated with many neurological disorders [29,30], we focused our functional analysis of TDP-43 on dendrites
We found that compared with wildtype ddaE neurons (Figure 4A), loss of Drosophila TDP-43 (dTDP-43) function in ddaE neurons reduced dendritic branching (Figure 4B), consistent with the genetic analysis of these neurons in dTDP-43Q367X homozygous mutant larvae (Figure 3). dTDP-43Q367X mutant ddaE neurons in the A3 segment had fewer dendritic ends than wildtype neurons labeled by Mosaic analysis with a repressible cell marker (MARCM) (23.3 ± 3.4 (n = 6) vs. 31.3 ± 4.9 (n = 6) (P < 0.001)
Summary
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. TDP-43 is depleted in the nucleus, suggesting a loss-of-function pathogenic mechanism. Frontotemporal lobar degeneration (FTLD) is a devastating age-dependent neurodegenerative condition primarily associated with impairments in cognition and social behaviors, as well as personality changes and other clinical abnormalities [1]. Increasing clinical, pathological, and molecular evidence indicates that FTD and amyotrophic lateral sclerosis (ALS) are closely related conditions [3]. Mutations in progranulin located on chromosome 17 cause FTD in some patients without tau pathology [8,9]. The pathogenic mechanism of FTD caused by progranulin deficiency is not known, but one of (page number not for citation purposes)
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