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Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4). Disruption of PERK signaling delays neurodegeneration without reducing JNK signaling. Furthermore, DLK is both sufficient for PERK activation and necessary for engaging the ISR subsequent to JNK-mediated retrograde injury signaling. These findings identify DLK as a central regulator of not only JNK but also PERK stress signaling in neurons, with both pathways contributing to neurodegeneration.<\/jats:p>","DOI":"10.7554\/elife.20725","type":"journal-article","created":{"date-parts":[[2017,4,17]],"date-time":"2017-04-17T20:00:15Z","timestamp":1492459215000},"source":"Crossref","is-referenced-by-count":79,"title":["Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult"],"prefix":"10.7554","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1547-6760","authenticated-orcid":true,"given":"Martin","family":"Larhammar","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Genentech, Inc., San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Huntwork-Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Genentech, Inc., San Francisco, United 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