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Home›Poly-lateral›Multiple pathways of toxicity induced by repeated aggregates of C9orf72 dipeptides and G (4) C (2) RNA in a cellular model

Multiple pathways of toxicity induced by repeated aggregates of C9orf72 dipeptides and G (4) C (2) RNA in a cellular model

By Allen Rodriquez
June 23, 2021
47
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This article was originally published here

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



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