Department of Neuroscience, Genentech, Inc., San Francisco, United States
Sarah Huntwork-Rodriguez
Department of Neuroscience, Genentech, Inc., San Francisco, United States
Zhiyu Jiang
Department of Neuroscience, Genentech, Inc., San Francisco, United States
Hilda Solanoy
Department of Neuroscience, Genentech, Inc., San Francisco, United States
Arundhati Sengupta Ghosh
Department of Neuroscience, Genentech, Inc., San Francisco, United States
Bei Wang
Department of Neuroscience, Genentech, Inc., San Francisco, United States
Joshua S Kaminker
Bioinformatics, Genentech, Inc., San Francisco, United States
Kevin Huang
Bioinformatics, Genentech, Inc., San Francisco, United States
Jeffrey Eastham-Anderson
Pathology, Genentech, Inc., San Francisco, United States
Michael Siu
Discovery Chemistry, Genentech, Inc., San Francisco, United States
Zora Modrusan
Molecular Biology, Genentech, Inc., San Francisco, United States
Madeline M Farley
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
Marc Tessier-Lavigne
Department of Neuroscience, Genentech, Inc., San Francisco, United States; Laboratory of Brain Development and Repair, The Rockefeller University, New York, United States
Department of Neuroscience, Genentech, Inc., San Francisco, United States; Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; OMNI Biomarkers Development, Genentech, Inc., San Francisco, United States
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.
