Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS
- 26 March 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 20 (12), 2308-2321
- https://doi.org/10.1093/hmg/ddr124
Abstract
The RNA-binding protein TDP-43 has been linked to amyotrophic lateral sclerosis (ALS) both as a causative locus and as a marker of pathology. With several missense mutations being identified within TDP-43, efforts have been directed towards generating animal models of ALS in mouse, zebrafish, Drosophila and worms. Previous loss of function and overexpression studies have shown that alterations in TDP-43 dosage recapitulate hallmark features of ALS pathology, including neuronal loss and locomotor dysfunction. Here we report a direct in vivo comparison between wild-type and A315T mutant TDP-43 overexpression in Drosophila neurons. We found that when expressed at comparable levels, wild-type TDP-43 exerts more severe effects on neuromuscular junction architecture, viability and motor neuron loss compared with the A315T allele. A subset of these differences can be compensated by higher levels of A315T expression, indicating a direct correlation between dosage and neurotoxic phenotypes. Interestingly, larval locomotion is the sole parameter that is more affected by the A315T allele than wild-type TDP-43. RNA interference and genetic interaction experiments indicate that TDP-43 overexpression mimics a loss-of-function phenotype and suggest a dominant-negative effect. Furthermore, we show that neuronal apoptosis does not require the cytoplasmic localization of TDP-43 and that its neurotoxicity is modulated by the proteasome, the HSP70 chaperone and the apoptosis pathway. Taken together, our findings provide novel insights into the phenotypic consequences of the A315T TDP-43 missense mutation and suggest that studies of individual mutations are critical for elucidating the molecular mechanisms of ALS and related neurodegenerative disorders.This publication has 56 references indexed in Scilit:
- Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALSNature, 2010
- A Drosophila model for TDP-43 proteinopathyProceedings of the National Academy of Sciences of the United States of America, 2010
- TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degenerationProceedings of the National Academy of Sciences of the United States of America, 2009
- Rethinking ALS: The FUS about TDP-43Cell, 2009
- Two German Kindreds With Familial Amyotrophic Lateral Sclerosis Due to TARDBP MutationsArchives of Neurology, 2008
- TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysisThe Lancet Neurology, 2008
- TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystanderMammalian Genome, 2008
- A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicityProceedings of the National Academy of Sciences of the United States of America, 2008
- TDP‐43 A315T mutation in familial motor neuron diseaseAnnals of Neurology, 2008
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993