Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Neurosci Bull. 2020 Sep;36(9):1057-1070. doi: 10.1007/s12264-020-00567-7. Epub 2020 Aug 29.


Since the discovery of the C9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients with C9ORF72 expansion show heterogeneous symptoms. Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients. Pathological and clinical features of C9ORF72 patients have been well mimicked via several models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated in C9ORF72 pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into non-C9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases.

Keywords: Amyotrophic lateral sclerosis; C9ORF72; Dipeptide repeat proteins; Frontotemporal dementia; Pathological inclusions.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Animals
  • C9orf72 Protein* / genetics
  • DNA Repeat Expansion
  • Frontotemporal Dementia* / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Proteins


  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins