PUBLICATION
Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
- Authors
- Parameswaran, J., Zhang, N., Braems, E., Tilahun, K., Pant, D.C., Yin, K., Asress, S., Heeren, K., Banerjee, A., Davis, E., Schwartz, S.L., Conn, G.L., Bassell, G.J., Van Den Bosch, L., Jiang, J.
- ID
- ZDB-PUB-230420-62
- Date
- 2023
- Source
- eLIFE 12: (Journal)
- Registered Authors
- Keywords
- neuroscience, zebrafish
- MeSH Terms
-
- Frontotemporal Dementia*/pathology
- C9orf72 Protein/genetics
- Amyotrophic Lateral Sclerosis*/pathology
- Zebrafish/genetics
- RNA, Small Interfering/genetics
- Animals
- DNA Repeat Expansion
- PubMed
- 37073950 Full text @ Elife
Citation
Parameswaran, J., Zhang, N., Braems, E., Tilahun, K., Pant, D.C., Yin, K., Asress, S., Heeren, K., Banerjee, A., Davis, E., Schwartz, S.L., Conn, G.L., Bassell, G.J., Van Den Bosch, L., Jiang, J. (2023) Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS. eLIFE. 12:.
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 granule formation. Reducing PKR levels with either siRNA or morpholinos mitigates integrated stress response and toxicity caused by the antisense C4G2 RNAs in cell lines, primary neurons, and zebrafish. 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 robustly activate the PKR/eIF2α pathway and induce aberrant stress granule formation. These results provide a mechanism by which antisense C4G2 repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9ORF72 repeat expansions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping