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

GGGGCC (G(4)C(2)) 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, a...

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Autores principales: Parameswaran, Janani, Zhang, Nancy, Braems, Elke, Tilahun, Kedamawit, Pant, Devesh C, Yin, Keena, Asress, Seneshaw, Heeren, Kara, Banerjee, Anwesha, Davis, Emma, Schwartz, Samantha L, Conn, Graeme L, Bassell, Gary J, Van Den Bosch, Ludo, Jiang, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10188109/
https://www.ncbi.nlm.nih.gov/pubmed/37073950
http://dx.doi.org/10.7554/eLife.85902
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author Parameswaran, Janani
Zhang, Nancy
Braems, Elke
Tilahun, Kedamawit
Pant, Devesh C
Yin, Keena
Asress, Seneshaw
Heeren, Kara
Banerjee, Anwesha
Davis, Emma
Schwartz, Samantha L
Conn, Graeme L
Bassell, Gary J
Van Den Bosch, Ludo
Jiang, Jie
author_facet Parameswaran, Janani
Zhang, Nancy
Braems, Elke
Tilahun, Kedamawit
Pant, Devesh C
Yin, Keena
Asress, Seneshaw
Heeren, Kara
Banerjee, Anwesha
Davis, Emma
Schwartz, Samantha L
Conn, Graeme L
Bassell, Gary J
Van Den Bosch, Ludo
Jiang, Jie
author_sort Parameswaran, Janani
collection PubMed
description GGGGCC (G(4)C(2)) 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 (C(4)G(2)) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9ORF72 antisense C(4)G(2) 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 C(4)G(2) 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 C(4)G(2), but not sense G(4)C(2), repeat expanded RNAs robustly activate the PKR/eIF2α pathway and induce aberrant stress granule formation. These results provide a mechanism by which antisense C(4)G(2) repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9ORF72 repeat expansions.
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spelling pubmed-101881092023-05-17 Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS Parameswaran, Janani Zhang, Nancy Braems, Elke Tilahun, Kedamawit Pant, Devesh C Yin, Keena Asress, Seneshaw Heeren, Kara Banerjee, Anwesha Davis, Emma Schwartz, Samantha L Conn, Graeme L Bassell, Gary J Van Den Bosch, Ludo Jiang, Jie eLife Neuroscience GGGGCC (G(4)C(2)) 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 (C(4)G(2)) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9ORF72 antisense C(4)G(2) 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 C(4)G(2) 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 C(4)G(2), but not sense G(4)C(2), repeat expanded RNAs robustly activate the PKR/eIF2α pathway and induce aberrant stress granule formation. These results provide a mechanism by which antisense C(4)G(2) repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9ORF72 repeat expansions. eLife Sciences Publications, Ltd 2023-04-19 /pmc/articles/PMC10188109/ /pubmed/37073950 http://dx.doi.org/10.7554/eLife.85902 Text en © 2023, Parameswaran et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Parameswaran, Janani
Zhang, Nancy
Braems, Elke
Tilahun, Kedamawit
Pant, Devesh C
Yin, Keena
Asress, Seneshaw
Heeren, Kara
Banerjee, Anwesha
Davis, Emma
Schwartz, Samantha L
Conn, Graeme L
Bassell, Gary J
Van Den Bosch, Ludo
Jiang, Jie
Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
title Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
title_full Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
title_fullStr Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
title_full_unstemmed Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
title_short Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
title_sort antisense, but not sense, repeat expanded rnas activate pkr/eif2α-dependent isr in c9orf72 ftd/als
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10188109/
https://www.ncbi.nlm.nih.gov/pubmed/37073950
http://dx.doi.org/10.7554/eLife.85902
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