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    Publication Date: 2016-03-19
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Rourke, J G -- Bogdanik, L -- Yanez, 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 -- GM085796/GM/NIGMS NIH HHS/ -- NS069669/NS/NINDS NIH HHS/ -- NS078398/NS/NINDS NIH HHS/ -- NS087351/NS/NINDS NIH HHS/ -- UL1TR000124/TR/NCATS NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):1324-9. doi: 10.1126/science.aaf1064.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. ; The Jackson Laboratory, Bar Harbor, ME, USA. ; Division of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. ; Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26989253" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/immunology ; Amyotrophic Lateral Sclerosis/genetics/*immunology ; Animals ; Frontotemporal Dementia/genetics/*immunology ; Gene Knockdown Techniques ; Guanine Nucleotide Exchange Factors/genetics/*physiology ; Heterozygote ; Humans ; Lymphatic Diseases/genetics/immunology ; Macrophages/*immunology ; Mice ; Mice, Knockout ; Microglia/*immunology ; Myeloid Cells/*immunology ; Proteins/genetics/*physiology ; Rats ; Splenomegaly/genetics/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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