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Neurosci Lett. 2019 Nov 20;713:134523. doi: 10.1016/j.neulet.2019.134523. Epub 2019 Sep 27.

C9ORF72 protein function and immune dysregulation in amyotrophic lateral sclerosis.

Author information

1
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Neuroscience, Amgen Inc., Cambridge, MA, USA.
2
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: ichida@usc.edu.

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing disease that affects upper and lower motor neurons eventually leading to paralysis and death by respiratory dysfunction. The most common genetic variant among ALS patients is a hexanucleotide repeat expansion within the first intron of the gene C9ORF72. This expansion elicits a complex cascade of events as a result of both gain- and loss-of-function mechanisms that contribute to neurodegeneration. Increasing evidence suggests that this repeat expansion in C9ORF72 also influences the immune homeostasis. In this review, we consolidate the current understanding of C9ORF72-mediated pathogenesis in both the central nervous system and peripheral immune system and propose mechanisms by which the immune system contributes to ALS.

KEYWORDS:

Amyotrophic lateral sclerosis; C9ORF72; Immunology; Neurodegeneration; Proteostasis

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