Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans

PLoS One. 2013 Dec 12;8(12):e83450. doi: 10.1371/journal.pone.0083450. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans Proteins*
  • Caenorhabditis elegans* / genetics
  • Caenorhabditis elegans* / metabolism
  • GABAergic Neurons* / metabolism
  • GABAergic Neurons* / pathology
  • Gene Deletion*
  • Motor Neuron Disease* / genetics
  • Motor Neuron Disease* / metabolism
  • Motor Neuron Disease* / pathology
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Osmotic Pressure*

Substances

  • Caenorhabditis elegans Proteins

Grant support

M.T. was supported by a RMGA scholarship. J.A.P. is a CIHR New Investigator. This research was supported by the CHUM Foundation, ALS Canada, and the Muscular Dystrophy Association (USA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.