Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G4C2 RNA in a cellular model

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 to...

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Bibliographic Details
Published in:eLife 2021-06, Vol.10
Main Authors: Frottin, Frédéric, Pérez-Berlanga, Manuela, Hartl, F Ulrich, Hipp, Mark S
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Biochemistry and Chemical Biology
Cell viability
Cytoplasm
Dementia disorders
Frontotemporal dementia
mRNA
neurodegeneration
Neuroscience
Nucleoli
Pathology
protein aggregation
Protein biosynthesis
Protein transport
Proteins
Quality control
Toxicity
Translation
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.62718