Figure 2.

NMD inhibition by C9orf72 R-DPRs drives a positive feedback loop. In normal neurons, cytoplasmic intron-retaining mRNAs are efficiently detected and degraded by NMD. In neurons carrying the C9orf72 hexanucleotide repeat expansion, however, RAN translation of the repeat intron-retaining C9orf72 mRNAs produces R-DPRs, which inhibits global translation and NMD. This global NMD deficit allows more aberrant RNAs, presumably including the repeat-containing C9orf72 mRNA, to accumulate in cytoplasm. Excessive aberrant RNAs may also in turn overload the already reduced NMD capacity in C9ALS/FTD neurons.