Multiple pathways of toxicity induced by <i>C9orf72</i> dipeptide repeat aggregates and G<sub>4</sub>C<sub>2</sub> RNA in a cellular model.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34161229.
- Also identified by DOI 10.7554/eLife.62718 and PMC identifier 8221807.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G<sub>4</sub>C<sub>2</sub> repeat expansion in the <i>C9orf72</i> 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<sub>4</sub>C<sub>2</sub> 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<sub>4</sub>C<sub>2</sub> 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<sub>4</sub>C<sub>2</sub> 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<sub>4</sub>C<sub>2</sub> RNA predominate in the cellular model used, DPRs exert additive effects that may contribute to pathology.
Medical subject headings
- C9orf72 Protein
- Dipeptides
- RNA
- RNA Transport