Deletion of C9ORF72 Results in Motor Neuron Degeneration and Stress Sensitivity in C. elegans
Open accessAbstract
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.
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Deletion of the zebrafish and C. elegans homologs of C9orf72 results in impaired locomotion and motor axon degeneration, implying that the C9orf72 protein is essential for motor neuron function and survival in these systems.
“Deletion of the zebrafish and C. elegans homologs of C9orf72 results in impaired locomotion and motor axon degeneration [182,183], implying that the C9orf72 protein is essential for motor neuron function and survival in these systems.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [183]
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References 38 · Cited by 183
- Authors
- Therrien, M., Rouleau, G. A., Dion, P. A., & Parker, J. A.
- Affiliations
- Centre Hospitalier de l’Université de Montréal (CA)
- Montreal Neurological Institute and Hospital (CA)
- Corresponding author
- Parker, J. Alex
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-12-12
- Volume
- 8
- Issue
- 12
- Pages
- e83450
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3861484
- OpenAlex
- W2017916137
- Cited by
- 183
- References
- 38
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 12 · 2022: 7 · 2021: 18 · 2020: 25 · 2019: 12 · 2018: 17 · 2017: 12 · 2016: 33 · 2015: 18 · 2014: 13
- FWCI
- 13.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship@McGill (McGill) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Muscular Dystrophy Association
- ALS Society of Canada
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- C9orf72, amyotrophic lateral sclerosis, motor neuron degeneration, GABAergic motor neurons, GGGGCC repeat expansion, loss-of-function mutations, osmotic stress, neurodegeneration, motility defects, paralysis, Caenorhabditis elegans model
- MeSH terms
- Animals, Motor Neurons, Osmotic Pressure, Motor Neuron Disease, Caenorhabditis elegans, Gene Deletion, Caenorhabditis elegans Proteins, GABAergic Neurons
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