PT  - JOURNAL ARTICLE
AU  - Frédéric Frottin
AU  - Manuela Pérez-Berlanga
AU  - F. Ulrich Hartl
AU  - Mark S. Hipp
TI  - Multiple pathways of toxicity induced by <em>C9orf72</em> dipeptide repeat aggregates and G<sub>4</sub>C<sub>2</sub> RNA in a cellular model
AID  - 10.1101/2020.09.14.297036
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.14.297036
4099  - http://biorxiv.org/content/early/2020/09/16/2020.09.14.297036.short
4100  - http://biorxiv.org/content/early/2020/09/16/2020.09.14.297036.full
AB  - The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G4C2 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 G4C2 RNA. Here we analyzed in a cellular model the relative toxicity of DPRs and RNA. Cytoplasmic poly-GA aggregates, generated in the absence of G4C2 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 G4C2 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 G4C2 RNA predominate, DPRs exert additive effects that may contribute to pathology.