C9orf72 is required for proper macrophage and microglial function in mice

Author:

O’Rourke J. G.1,Bogdanik L.2,Yáñez A.1,Lall D.1,Wolf A. J.3,Muhammad A. K. M. G.1,Ho R.1,Carmona S.1,Vit J.P.3,Zarrow J.1,Kim K. J.1,Bell S.1,Harms M. B.4,Miller T. M.4,Dangler C. A.2,Underhill D. M.3,Goodridge H. S.1,Lutz C. M.2,Baloh R. H.15

Affiliation:

1. Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.

2. The Jackson Laboratory, Bar Harbor, ME, USA.

3. Division of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.

4. Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

5. Department of Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.

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

Funder

NIH

Robert and Louise Schwab family

Cedars-Sinai ALS Research Fund

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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