Fig. 1.

Overview of the different disease mechanisms at play in C9orf72-ALS/FTD. First, the (GGGGCC)n hexanucleotide repeat expansion could reduce transcription of the C9orf72 gene leading to reduced C9orf72 protein levels (haploinsufficiency) that may ultimately cause dysfunction of the autophagy-lysosome pathway. Second, bidirectional transcription of the repeat expansion forms sense (GGGGCC) and antisense (CCCCGG) RNA transcripts that form secondary structures and may cause RNA toxicity by sequestering essential RNA-binding proteins (RBPs). Finally, unconventional repeat-associated non-ATG (RAN) translation produces toxic dipeptide repeat proteins (DPRs): polyGP, polyGR and polyGA from the sense strand and polyGP, polyPR and polyPA from the antisense strand. These toxic DPRs are able to form aggregates and may affect several essential cellular pathways such as mitochondrial function, axonal transport, proteasome function and protein translation. Moreover, these three mechanisms may work separately or in synergy to cause alterations in nuclear-cytoplasmic transport, TDP-43 subcellular localization and stress granule dynamics that are toxic to motor neurons. DPR: dipeptide repeat protein; RAN: repeat associated non-ATG translation; RBP: RNA-binding protein; TDP-43: TAR DNA-binding protein 43