Cited by 221Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesHereditary Neurological Disorders

Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

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Zhu, Qiang, Jiang, Jie, Gendron, Tania F., McAlonis-Downes, Melissa, Jiang, Lulin, Taylor, Amy, Diaz Garcia, Sandra, Ghosh Dastidar, Somasish +10 more·2020·Nature Neuroscience

Abstract

Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.

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  • Loss of C9orf72 function and consequent impairment in autophagy may enhance DPR accumulation in C9orf72 mutation carriers, acting synergistically to accentuate neurodegeneration.

    “Furthermore, the loss of C9orf72 function and consequent impairment in autophagy may enhance DPR accumulation in C9orf72 mutation carriers, acting synergistically to accentuate neurodegeneration [154,172,173].”
  • Loss of endogenous murine C9orf72 results in glial activation, impaired autophagy and toxicity when combined with the C9orf72 expansion mutation.

    “On the other hand, loss of endogenous murine C9orf72 results in glial activation, impaired autophagy and toxicity when combined with the C9orf72 expansion mutation [173].”
  • Loss of wild-type C9orf72 function exacerbates the neurotoxic effects of a C9orf72 mutant allele, bearing hexanucleotide expansions, by repressing autophagy.

    “Consistently, it has been recently observed that loss of wild‐type C9orf72 function exacerbates the neurotoxic effects of a C9orf72 mutant allele, bearing hexanucleotide expansions, by repressing autophagy (Zhu et al, 2020).”

    From Autophagy in major human diseases (2021) · cites this paper as Zhu et al, 2020

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Authors
Zhu, Q., Jiang, J., Gendron, T. F., McAlonis-Downes, M., Jiang, L., Taylor, A., Diaz Garcia, S., Ghosh Dastidar, S., Rodriguez, M. J., King, P., Zhang, Y., La Spada, A. R., Xu, H., Petrucelli, L., Ravits, J., Da Cruz, S., Lagier-Tourenne, C., & Cleveland, D. W.
Affiliations
  • University of California San Diego (US)
  • Emory University (US)
  • Mayo Clinic in Florida (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author
Cleveland, Don W.
Venue
Nature Neuroscience
Published
2020-04-13
Volume
23
Issue
5
Pages
615-624
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W3015315508
Cited by
220
References
60
Citations by year
2026: 10 · 2025: 26 · 2024: 28 · 2023: 40 · 2022: 35 · 2021: 49 · 2020: 31 · 2019: 1
FWCI
16.88
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion)
Funders
  • Amyotrophic Lateral Sclerosis Association (18-IIA-407, 2313)
  • Muscular Dystrophy Association (479769)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (P01-NS099114, P01-NS084974, R01-NS088689, R01-NS27036, R01-NS087227)
  • Target ALS
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
C9orf72, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, dipeptide repeat proteins, autophagy, transgenic mouse model, cognitive impairment, hippocampal neuronal loss, glial activation
MeSH terms
C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, DNA Repeat Expansion, Mice, Frontotemporal Dementia

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