Article Dans Une Revue eLife Année : 2021

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.
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hal-04950972 , version 1 (17-02-2025)

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Frédéric Frottin, Manuela Pérez-Berlanga, F Ulrich Hartl, Mark S Hipp. Multiple pathways of toxicity induced by $C9orf72$ dipeptide repeat aggregates and G$_4$C$_2$ RNA in a cellular model. eLife, 2021, 10, pp.e62718. ⟨10.7554/eLife.62718⟩. ⟨hal-04950972⟩
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