Multiple pathways of toxicity induced by $C9orf72$ dipeptide repeat aggregates and G$_4$C$_2$ RNA in a cellular model
Résumé
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 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 G$_4$C$_2$ RNA. Here, we analyzed in a cellular model the relative toxicity of DPRs and RNA. Cytoplasmic poly-GA aggregates, generated in the absence of G$_4$C$_2$ 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 G$_4$C$_2$ 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 G$_4$C$_2$ RNA predominate in the cellular model used, DPRs exert additive effects that may contribute to pathology.
Domaines
Sciences du Vivant [q-bio]Origine | Fichiers produits par l'(les) auteur(s) |
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