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

Frédéric Frottin*, Manuela Pérez-Berlanga, F Ulrich Hartl*, Mark S Hipp*

*Corresponding author voor dit werk

    Onderzoeksoutput: ArticleAcademicpeer review

    18 Citaten (Scopus)
    106 Downloads (Pure)

    Samenvatting

    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 in the cellular model used, DPRs exert additive effects that may contribute to pathology.
    Originele taal-2English
    Artikelnummere62718
    TijdschrifteLife
    Volume10
    DOI's
    StatusPublished - 23-jun.-2021

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