C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production and glomerulonephropathy in mice
Open accessAbstract
The expansion of a hexanucleotide (GGGGCC) repeat in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown. To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line. Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation and increased plasma cells. Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy. Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence. We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology.
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Deletion of the mouse C9orf72 ortholog leads to splenomegaly, lymphadenopathy, dysregulation of macrophages and microglia, and excess production of inflammatory cytokines.
“In contrast, deletion of the mouse C9orf72 ortholog leads to splenomegaly, lymphadenopathy, dysregulation of macrophages and microglia, and excess production of inflammatory cytokines [184–187].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [184]
c9orf72 knockout animals exhibit a shortened lifespan, but no specific neuronal defects have been identified in these mice.
“While c9orf72 knockout animals exhibit a shortened lifespan [184,185,187], no specific neuronal defects have been identified in these mice.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [184]
C9orf72-deficient mice display lysosomal accumulation and a hyperactive immune response characterized by enhanced production of IL1B and IL6.
“C9orf72-deficient mice display lysosomal accumulation and a hyperactive immune response characterized by enhanced production of IL1B and IL6 [184,185,187,439],”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [184]
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References 67 · Cited by 263
- Authors
- Atanasio, A., Decman, V., White, D., Ramos, M., Ikiz, B., Lee, H.-C., Siao, C.-J., Brydges, S., LaRosa, E., Bai, Y., Fury, W., Burfeind, P., Zamfirova, R., Warshaw, G., Orengo, J., Oyejide, A., Fralish, M., Auerbach, W., Poueymirou, W., Freudenberg, J., Gong, G., Zambrowicz, B., Valenzuela, D., Yancopoulos, G., Murphy, A., Thurston, G., & Lai, K.-M. V.
- Affiliations
- Regeneron (United States) (US)
- Corresponding author
- Lai, Ka-Man Venus
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-03-16
- Volume
- 6
- Issue
- 1
- Pages
- 23204-23204
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4793236
- OpenAlex
- W2297261057
- Cited by
- 263
- References
- 67
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 18 · 2023: 20 · 2022: 24 · 2021: 39 · 2020: 27 · 2019: 27 · 2018: 33 · 2017: 24 · 2016: 25
- FWCI
- 27.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- C9orf72, haploinsufficiency, immune dysregulation, autoantibodies, glomerulonephropathy, systemic lupus erythematosus, amyotrophic lateral sclerosis, frontotemporal dementia, myeloid expansion, T cell activation, plasma cells, immune homeostasis, hexanucleotide repeat expansion
- MeSH terms
- C9orf72 Protein, Animals, Autoantibodies, Female, Lupus Erythematosus, Systemic, Lymphocyte Activation, Lymphoid Tissue, Macrophages, Male, Mice, Inbred C57BL, Plasma Cells, Glomerulonephritis, Membranoproliferative, Autoimmunity, Cytokines, Sequence Analysis, RNA, Mice, Knockout, Guanine Nucleotide Exchange Factors, Mice, 129 Strain, Transcriptome
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