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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\n                    <jats:sub>4<\/jats:sub>\n                    G\n                    <jats:sub>2<\/jats:sub>\n                    ) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    antisense C\n                    <jats:sub>4<\/jats:sub>\n                    G\n                    <jats:sub>2<\/jats:sub>\n                    repeat expanded RNAs trigger the activation of the PKR\/eIF2\u03b1-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\n                    <jats:sub>4<\/jats:sub>\n                    G\n                    <jats:sub>2<\/jats:sub>\n                    RNAs in cell lines, primary neurons, and zebrafish. Increased phosphorylation of PKR\/eIF2\u03b1 is also observed in the frontal cortex of\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    FTD\/ALS patients. Finally, only antisense C\n                    <jats:sub>4<\/jats:sub>\n                    G\n                    <jats:sub>2<\/jats:sub>\n                    , but not sense G\n                    <jats:sub>4<\/jats:sub>\n                    C\n                    <jats:sub>2<\/jats:sub>\n                    , repeat expanded RNAs robustly activate the PKR\/eIF2\u03b1 pathway and induce aberrant stress granule formation. These results provide a mechanism by which antisense C\n                    <jats:sub>4<\/jats:sub>\n                    G\n                    <jats:sub>2<\/jats:sub>\n                    repeat expanded RNAs elicit neuronal toxicity in FTD\/ALS caused by\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    repeat expansions.\n                  <\/jats:p>","DOI":"10.7554\/elife.85902","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T06:15:17Z","timestamp":1681884917000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.85902","source":"Crossref","is-referenced-by-count":24,"title":["Antisense, but not sense, repeat expanded RNAs activate PKR\/eIF2\u03b1-dependent ISR in C9ORF72 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