Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo
Open Access
- 3 December 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (4), 671-683
- https://doi.org/10.1093/hmg/ddp534
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.Keywords
This publication has 69 references indexed in Scilit:
- Overexpression of mutant superoxide dismutase 1 causes a motor axonopathy in the zebrafishHuman Molecular Genetics, 2007
- Transgenic mouse models of amyotrophic lateral sclerosisBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006
- ALS: A Disease of Motor Neurons and Their Nonneuronal NeighborsNeuron, 2006
- Genetics of familial and sporadic amyotrophic lateral sclerosisBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006
- A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral SclerosisAmerican Journal of Human Genetics, 2004
- DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4)American Journal of Human Genetics, 2004
- Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS)Proceedings of the National Academy of Sciences, 2002
- A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2Nature Genetics, 2001
- Motor Neuron Degeneration in Mice that Express a Human Cu,Zn Superoxide Dismutase MutationScience, 1994
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993