C9ORF72 protein function and immune dysregulation in amyotrophic lateral sclerosis

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / immunology*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • C9orf72 Protein / genetics
  • C9orf72 Protein / immunology*
  • C9orf72 Protein / physiology*
  • DNA Repeat Expansion
  • Humans
  • Nerve Degeneration / physiopathology*


  • C9orf72 Protein
  • C9orf72 protein, human