RT Journal Article
SR Electronic
T1 Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent integrated stress response in C9orf72 FTD/ALS
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.06.495030
DO 10.1101/2022.06.06.495030
A1 Parameswaran, Janani
A1 Zhang, Nancy
A1 Tilahun, Kedamawit
A1 Pant, Devesh C.
A1 Chilukuri, Ganesh
A1 Asress, Seneshaw
A1 Banerjee, Anwesha
A1 Davis, Emma
A1 Schwartz, Samantha L.
A1 Conn, Graeme L.
A1 Bassell, Gary J.
A1 Jiang, Jie
YR 2022
UL http://biorxiv.org/content/early/2022/06/06/2022.06.06.495030.abstract
AB 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 (C4G2) antisense 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 granule formation. Increased phosphorylation of PKR/eIF2α is also observed in the frontal cortex of C9orf72 FTD/ALS patients. Finally, only antisense (C4G2), but not sense (G4C2), repeat expanded RNAs can activate the PKR/eIF2α pathway. These results provide a mechanism by which antisense repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9orf72 repeat expansions.Competing Interest StatementThe authors have declared no competing interest.