Cited by 550Amyotrophic Lateral Sclerosis ResearchNeuroinflammation and Neurodegeneration MechanismsGenetic Neurodegenerative Diseases

C9orf72 is required for proper macrophage and microglial function in mice

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O’Rourke, J. G., Bogdanik, L., Yáñez, A., Lall, D., Wolf, A. J., Muhammad, A. K. M. G., Ho, R., Carmona, S. +11 more·2016·Science

Abstract

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 measured
  • C9orf72 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).”
  • 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],”
  • C9orf72 is important for maintaining microglia homeostasis.

    “C9orf72 is important for maintaining microglia homeostasis.”
  • 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”

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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.
Venue
Science
Published
2016-03-18
Volume
351
Issue
6279
Pages
1324-1329
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
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
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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