title: Mutant TDP-43 and FUS cause age-dependent paralysis and neurodegeneration in C. elegans.
abstract: Mutations in the DNA/RNA binding proteins TDP-43 and FUS are associated with Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. Intracellular accumulations of wild type TDP-43 and FUS are observed in a growing number of late-onset diseases suggesting that TDP-43 and FUS proteinopathies may contribute to multiple neurodegenerative diseases. To better understand the mechanisms of TDP-43 and FUS toxicity we have created transgenic Caenorhabditis elegans strains that express full-length, untagged human TDP-43 and FUS in the worm's GABAergic motor neurons. Transgenic worms expressing mutant TDP-43 and FUS display adult-onset, age-dependent loss of motility, progressive paralysis and neuronal degeneration that is distinct from wild type alleles. Additionally, mutant TDP-43 and FUS proteins are highly insoluble while wild type proteins remain soluble suggesting that protein misfolding may contribute to toxicity. Populations of mutant TDP-43 and FUS transgenics grown on solid media become paralyzed over 7 to 12 days. We have developed a liquid culture assay where the paralysis phenotype evolves over several hours. We introduce C. elegans transgenics for mutant TDP-43 and FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening.
authors.affiliation: University of Montreal Hospital Centre, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vaccaro
authors.forename: Arnaud
authors.initials: A
authors.lastname: Tauffenberger
authors.forename: Dina
authors.initials: D
authors.lastname: Aggad
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008136:Longevity; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism*; D009410:Nerve Degeneration / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010243:Paralysis / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010641:Phenotype; D020836:Protein Structure, Quaternary; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D013194:Staining and Labeling; D009435:Synaptic Transmission; D019076:Transgenes / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D034702:RNA-Binding Protein FUS; D005680:gamma-Aminobutyric Acid