C9orf72-mediated ALS and FTD: multiple pathways to disease

Nat Rev Neurol. 2018 Sep;14(9):544-558. doi: 10.1038/s41582-018-0047-2.


The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Amyotrophic Lateral Sclerosis* / pathology
  • Amyotrophic Lateral Sclerosis* / therapy
  • Animals
  • C9orf72 Protein* / genetics
  • Disease Models, Animal*
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Dementia* / metabolism
  • Frontotemporal Dementia* / pathology
  • Frontotemporal Dementia* / therapy
  • Humans


  • C9orf72 Protein
  • C9orf72 protein, human