PUBLICATION

Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo

Authors
Kabashi, E., Lin, L., Tradewell, M.L., Dion, P.A., Bercier, V., Bourgouin, P., Rochefort, D., Bel Hadj, S., Durham, H.D., Vande Velde, C., Rouleau, G.A., and Drapeau, P.
ID
ZDB-PUB-091215-41
Date
2010
Source
Human molecular genetics   19(4): 671-683 (Journal)
Registered Authors
Drapeau, Pierre
Keywords
none
MeSH Terms
  • Amyotrophic Lateral Sclerosis/genetics
  • Amyotrophic Lateral Sclerosis/metabolism
  • Amyotrophic Lateral Sclerosis/physiopathology*
  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/metabolism*
  • Humans
  • Mice
  • Motor Activity*
  • Motor Neurons/metabolism
  • Mutation*
  • Zebrafish/genetics
  • Zebrafish/physiology
PubMed
19959528 Full text @ Hum. Mol. Genet.
Abstract
TDP-43 has been found in inclusion bodies of multiple neurological disorders, including amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease and Alzheimer's disease. Mutations in the TDP-43 encoding gene, TARDBP, have been subsequently reported in sporadic and familial ALS patients. In order to investigate the pathogenic nature of these mutants, the effects of three consistently reported TARDBP mutations (A315T, G348C & A382T) were tested in cell lines, primary cultured motor neurons and living zebrafish embryos. Each of the three mutants and wild type (WT) human TDP-43 localized to nuclei when expressed in COS1 and Neuro2A cells by transient transfection. However, when expressed in motor neurons from dissociated spinal cord cultures these mutant TARDBP alleles, but less so for WT TARDBP, were neurotoxic, concomitant with perinuclear localization and aggregation of TDP-43. Finally, overexpression of mutant, but less so of WT, human TARDBP caused a motor phenotype in zebrafish (Danio rerio) embryos consisting of shorter motor neuronal axons, premature and excessive branching as well as swimming deficits. Interestingly, knock-down of zebrafisfh tardbp led to a similar phenotype, which was rescued by co-expressing WT but not mutant human TARDBP. Together these approaches showed that TARDBP mutations cause motor neuron defects and toxicity, suggesting that both a toxic gain of function as well as a novel loss of function may be involved in the molecular mechanism by which mutant TDP-43 contributes to disease pathogenesis.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes