title: C9orf72 is required for proper macrophage and microglial function in mice.
abstract: Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: O'Rourke
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bogdanik
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: A
authors.initials: A
authors.lastname: Yáñez
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lall
authors.affiliation: Division of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Wolf
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: A K M G
authors.initials: AK
authors.lastname: Muhammad
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ho
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: S
authors.initials: S
authors.lastname: Carmona
authors.affiliation: Division of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Vit
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zarrow
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bell
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Harms
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Miller
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Dangler
authors.affiliation: Division of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Underhill
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Goodridge
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Lutz
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Department of Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Baloh
mesh_terms: D000375:Aging / Q000276:immunology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000073885:C9orf72 Protein; D057180:Frontotemporal Dementia / Q000235:genetics / Q000276:immunology*; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D006801:Humans; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C000606498:C9orf72 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins