Phosphorylation Promotes Neurotoxicity in aCaenorhabditis elegansModel of TDP-43 Proteinopathy
Open Access
- 1 December 2010
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 30 (48), 16208-16219
- https://doi.org/10.1523/jneurosci.2911-10.2010
Abstract
Neurodegenerative disorders characterized by neuronal and glial lesions containing aggregated pathological TDP-43 protein in the cytoplasm, nucleus, or neurites are collectively referred to as TDP-43 proteinopathies. Lesions containing aggregated TDP-43 protein are a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). In addition, mutations in human TDP-43 cause ALS. We have developed aCaenorhabditis elegansmodel of TDP-43 proteinopathies to study the cellular, molecular, and genetic underpinnings of TDP-43-mediated neurotoxicity. Expression of normal human TDP-43 in allC. elegansneurons causes moderate motor defects, whereas ALS-mutant G290A, A315T, or M337V TDP-43 transgenes cause severe motor dysfunction. The model recapitulates some characteristic features of ALS and FTLD-U including age-induced decline in motor function, decreased life span, and degeneration of motor neurons accompanied by hyperphosphorylation, truncation, and ubiquitination of TDP-43 protein that accumulates in detergent-insoluble protein deposits. InC. elegans, TDP-43 neurotoxicity is independent of activity of the cell death caspase CED-3. Furthermore, phosphorylation of TDP-43 at serine residues 409/410 drives mutant TDP-43 toxicity. This model provides a tractable system for additional dissection of the cellular and molecular mechanisms underlying TDP-43 neuropathology.Keywords
This publication has 59 references indexed in Scilit:
- 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
- Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicityProceedings of the National Academy of Sciences of the United States of America, 2009
- Mimicking Aspects of Frontotemporal Lobar Degeneration and Lou Gehrig's Disease in Rats via TDP-43 OverexpressionMolecular Therapy, 2009
- Combined informatic and expression screen identifies the novel DAF-16 target HLH-13Developmental Biology, 2009
- Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathiesActa Neuropathologica, 2009
- Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosisAnnals of Neurology, 2008
- TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysisThe Lancet Neurology, 2008
- TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expressionProceedings 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
- TDP-43: a novel neurodegenerative proteinopathyCurrent Opinion in Neurobiology, 2007