Abstract
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.
Highlights
Expansion of a GGGGCC hexanucleotide repeat within the first intron of the C9orf72 gene is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011)
We have employed a cellular model to differentiate possible mechanisms of toxicity exerted by expansion of the G4C2 hexanucleotide tract within the C9orf72 locus, the most frequent genetic cause of ALS and FTD (DeJesus-Hernandez et al, 2011; Renton et al, 2011)
Our results demonstrated that the G4C2 expansion causes toxicity in our cellular system in a manner dependent on both aggregates of G4C2-encoded dipeptide repeat (DPR) proteins and the G4C2 repeat mRNA
Summary
Expansion of a GGGGCC hexanucleotide repeat (hereafter G4C2) within the first intron of the C9orf gene is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011). In patient brain and cellular models, DPRs accumulate in deposits that can be found in the nucleus and cytoplasm, including neurites (Ash et al, 2013; Gendron et al, 2013; Mackenzie et al, 2015; Mori et al, 2013a; Mori et al, 2013c; Schludi et al, 2015; Zu et al, 2013). Poly-GA aggregates are localized mainly in the cytoplasm (Davidson et al, 2016; Lee et al, 2017; Mackenzie et al, 2015; Zhang et al, 2016), whereas arginine-containing DPRs (R-DPRs; poly-GR and poly-PR) accumulate in the nucleus
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