Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G4C2 RNA in a cellular model

The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G 4 C 2 repeat expansion in the C9orf72 gene. This gives rise to translation aggregating dipeptide (DPR) proteins, including poly-GA as abundant species. However, gain toxic function effects have been attributed either DPRs or pathological RNA. Here, we analyzed cellular model relative toxicity Cytoplasmic aggregates, generated absence RNA, interfered with nucleocytoplasmic protein transport, but had little effect on cell viability. In contrast, nuclear was more toxic, impairing nucleolar quality control biosynthesis. Production RNA strongly reduced viability independent DPR caused pronounced inhibition mRNA export biogenesis. Thus, while predominate used, exert additive that may contribute pathology.