C9orf72 is required for proper macrophage and microglial function in mice
Open accessAbstract
Linking neurodegeneration and immune cells: The expansion of a repetitive DNA sequence in the C9orf72 gene is the major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Although the expansion decreases C9orf72 expression, most research has focused on the toxic RNA and protein products it creates in neurons. O'Rourke et al. found that C9orf72 unexpectedly plays a key role in innate immune cells. Loss of C9orf72 in mice led to macrophage and microglial dysfunction and age-related neuroinflammation. This raises the possibility of a “dual-effect” disease mechanism, in which toxic byproducts in neurons are combined with microglial dysfunction from decreased C9orf72 expression, together promoting neurodegeneration. Science , this issue p. 1324
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Expansions in C9ORF72 have effects on microglial function as well as neurons, and risk variants for FTD in TREM2 are associated with microglial activation.
“Expansions in C9ORF72 have effects on microglial function as well as neurons (O’Rouke et al., 2016), and risk variants for FTD in TREM2 are associated with microglial activation (Giraldo et al., 2013).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as O’Rouke et al., 2016
The Abstract reports altered microglial function after loss of C9orf72 in mice and says this may contribute to neurodegeneration in expansion carriers. The concluding passage proposes effects in both neurons and microglia as a possible dual-effect mechanism; it does not establish that repeat expansions themselves affect microglial function. The separately cited TREM2 clause is not attributed to this paper. (LLM, conf=0.86)
Experimental — accuracy not yet measuredC9orf72 is required for normal myeloid cell function, and altered microglial function may contribute to neurodegeneration in carriers of C9orf72 expansion.
“C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in carriers of C9orf72 expansion (153).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [153]
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 [439]
C9orf72 is important for maintaining microglia homeostasis.
“C9orf72 is important for maintaining microglia homeostasis.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [361]
In C9orf72-/- mice, progressive splenomegaly, lymphadenopathy, and upregulation of pro-inflammatory cytokines were observed at the periphery, while brain and spinal cord microglia showed an inflammatory state.
“In the C9orf72–/– mice, progressive splenomegaly, lymphadenopathy, and upregulation of pro-inflammatory cytokines were observed at the periphery, while brain and spinal cord microglia showed an inflammatory state.361”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [361]
Decreased C9orf72 expression in C9-ALS led to altered microglial function and increased microglial activation.
“Transcriptome and histologic analyses of postmortem tissue from patients with ALS carrying the C9orf72 expansion (C9-ALS) found that decreased C9orf72 expression in C9-ALS led to altered microglial function and increased microglial activation.309,361”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [361]
Microglia show higher levels of C9orf72 expression than other cell types in the brain.
“Microglia showed higher levels of C9orf72 expression than other cell types in the brain,361”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [361]
C9orf72 is required for normal immune function of myeloid cells.
“and research suggests that C9orf72 is required for the normal immune function of myeloid cells.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [361]
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- Authors
- O’Rourke, J. G., Bogdanik, L., Yáñez, A., Lall, D., Wolf, A. J., Muhammad, A. K. M. G., Ho, R., Carmona, S., Vit, J. P., Zarrow, J., Kim, K. J., Bell, S., Harms, M. B., Miller, T. M., Dangler, C. A., Underhill, D. M., Goodridge, H. S., Lutz, C. M., & Baloh, R. H.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Jackson Laboratory (US)
- Washington University in St. Louis (US)
- Corresponding author
- Baloh, R. H.
- ORCID
- Venue
- Science
- Published
- 2016-03-18
- Volume
- 351
- Issue
- 6279
- Pages
- 1324-1329
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5120541
- OpenAlex
- W2304886140
- Cited by
- 550
- References
- 35
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 36 · 2023: 59 · 2022: 55 · 2021: 60 · 2020: 62 · 2019: 56 · 2018: 65 · 2017: 55 · 2016: 43
- FWCI
- 54.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, cc-by-nc)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- NIH (NS069669, NS087351, GM085796, NS078398, UL1TR000124)
- Robert and Louise Schwab family
- Cedars-Sinai ALS Research Fund
- 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, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, macrophages, microglia, myeloid cells, lysosomal accumulation, neuroinflammation, splenomegaly, lymphadenopathy, loss of function, neurodegeneration, mouse model
- MeSH terms
- C9orf72 Protein, Aging, Amyotrophic Lateral Sclerosis, Animals, Heterozygote, Humans, Lymphatic Diseases, Macrophages, Proteins, Splenomegaly, Microglia, Mice, Knockout, Guanine Nucleotide Exchange Factors, Myeloid Cells, Mice, Rats, Gene Knockdown Techniques, Frontotemporal Dementia
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