Evie. Jun 23, 2021; 10: e62718. doi: 10.7554 / eLife.62718.

ABSTRACT

The most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G₄VS₂ repeat the expansion in the C9orf72 uncomfortable. This expansion gives rise to the translation of repeated dipeptide protein (DPR) aggregation, including poly-GA as the most abundant species. However, the gain in toxic functional effects has been attributed to DPR or pathological G.₄VS₂ RNA. Here, we analyzed in a cellular model the relative toxicity of DPR and RNA. Cytoplasmic poly-GA aggregates, generated in the absence of G₄VS₂ RNA interfered with the transport of nucleocytoplasmic proteins, but had little effect on cell viability. In contrast, nuclear poly-GA was more toxic, impairing quality control of nucleolar proteins and protein biosynthesis. Manufacture of G₄VS₂ RNA strongly reduced the viability independent of DPR translation and caused a pronounced inhibition of nuclear mRNA export and protein biogenesis. Thus, while the toxic effects of G₄VS₂ RNA predominates in the cell model used, DPRs exert additive effects which may contribute to the pathology.

PMID:34161229 | DO I:10.7554 / eLife.62718