title: Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo.
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 and 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.
authors: Centre of Excellence in Neuromics, Department of Medicine, Université de Montré al,Montréal, Quebec, Canada.
authors: Edor
authors: E
authors: Kabashi
authors: Li
authors: L
authors: Lin
authors: Miranda L
authors: ML
authors: Tradewell
authors: Patrick A
authors: PA
authors: Dion
authors: Valérie
authors: V
authors: Bercier
authors: Patrick
authors: P
authors: Bourgouin
authors: Daniel
authors: D
authors: Rochefort
authors: Samar
authors: S
authors: Bel Hadj
authors: Heather D
authors: HD
authors: Durham
authors: Christine
authors: C
authors: Vande Velde
authors: Guy A
authors: GA
authors: Rouleau
authors: Pierre
authors: P
authors: Drapeau
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D015027:Zebrafish / Q000235:genetics / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins