Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS.

ABSTRACT: GGGGCC (G₄C₂) hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C₄G₂) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9ORF72 antisense C₄G₂ repeat expanded RNAs trigger the activation of the PKR/eIF2α-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG-initiated translation, leading to global translation inhibition and stress granul

SUBMITTER: Parameswaran J 

PROVIDER: S-EPMC10188109 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature