Phosphorylation promotes neurotoxicity in a Caenorhabditis elegans model of TDP-43 proteinopathy.
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 a Caenorhabditis elegans model of TDP-43 proteinopathies to study the cellular, molecular, and genetic underpinnings of TDP-43-mediated neurotoxicity. Expression of normal human TDP-43 in all C. elegans neurons 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. In C. 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.
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA.
Nicole F
NF
Liachko
Chris R
CR
Guthrie
Brian C
BC
Kraemer
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins