Multiple pathways of toxicity induced by dipeptide repeat aggregates and GC RNA in a cellular model.

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