TY - JOUR TI - Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult AU - Larhammar, Martin AU - Huntwork-Rodriguez, Sarah AU - Jiang, Zhiyu AU - Solanoy, Hilda AU - Sengupta Ghosh, Arundhati AU - Wang, Bei AU - Kaminker, Joshua S AU - Huang, Kevin AU - Eastham-Anderson, Jeffrey AU - Siu, Michael AU - Modrusan, Zora AU - Farley, Madeline M AU - Tessier-Lavigne, Marc AU - Lewcock, Joseph W AU - Watkins, Trent A A2 - Dillin, Andrew VL - 6 PY - 2017 DA - 2017/04/25 SP - e20725 C1 - eLife 2017;6:e20725 DO - 10.7554/eLife.20725 UR - https://doi.org/10.7554/eLife.20725 AB - The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. 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. KW - optic nerve KW - unfolded protein response KW - apoptosis KW - neurodegeneration KW - axonal injury KW - stress response JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -