title: Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans.
abstract: An expansion of the hexanucleotide GGGGCC repeat in the first intron of C9ORF72 gene was recently linked to amyotrophic lateral sclerosis. It is not known if the mutation results in a gain of function, a loss of function or if, perhaps both mechanisms are linked to pathogenesis. We generated a genetic model of ALS to explore the biological consequences of a null mutation of the Caenorhabditis elegans C9ORF72 orthologue, F18A1.6, also called alfa-1. alfa-1 mutants displayed age-dependent motility defects leading to paralysis and the specific degeneration of GABAergic motor neurons. alfa-1 mutants showed differential susceptibility to environmental stress where osmotic stress provoked neurodegeneration. Finally, we observed that the motor defects caused by loss of alfa-1 were additive with the toxicity caused by mutant TDP-43 proteins, but not by the mutant FUS proteins. These data suggest that a loss of alfa-1/C9ORF72 expression may contribute to motor neuron degeneration in a pathway associated with other known ALS genes.
authors.affiliation: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada ; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Therrien
authors.affiliation: Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec, Canada ; Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.affiliation: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada ; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec, Canada ; Département de neuroscience, Université de Montréal, Montréal, Québec, Canada.
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009997:Osmotic Pressure
chemical_list: D029742:Caenorhabditis elegans Proteins