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. Author manuscript; available in PMC: 2015 Mar 1.
Published in final edited form as: Acta Neuropathol. 2014 Jan 7;127(3):359–376. doi: 10.1007/s00401-013-1237-z

Figure 1. Potential mechanisms of disease in C9FTLD/ALS.

Figure 1

Expansion of the G4C2 C4G2 repeat within intron 1 of the C9ORF72 gene may cause C9FTLD/ALS through various mechanisms. 1) Abnormal DNA and histone methylation leads to a decrease in C9ORF72 mRNA expression which may consequently result in C9orf2 protein loss of function; 2) (G4C2)exp and (C4G2)exp transcripts are bound by select RNA-binding proteins and this may impair the ability of such proteins to bind their actual RNA targets. In addition, because (G4C2)exp and (C4G2)exp transcripts form nuclear foci, RNA-binding proteins that interact with these transcripts may too be sequestered in foci, also resulting in their loss of function; 3) In the cytosol, (G4C2)exp and (C4G2)exp transcripts are susceptible to repeat-associated non-ATG translation, producing poly(GA), poly(GP), poly(GR), poly(PR) and poly(PA) C9RAN proteins. Each C9RAN protein may have a different toxicity profile, and may contribute to neurodegeneration through the formation of soluble oligomers or their aggregation into insoluble inclusions within neurons.