Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult

eLife

Joseph W Lewcock¹  Joshua S Kaminker²  Kevin Huang²  Martin Larhammar³  Zhiyu Jiang³  Bei Wang³  Hilda Solanoy³  Trent A Watkins³  Sarah Huntwork-Rodriguez³  Arundhati Sengupta Ghosh³  Marc Tessier-Lavigne³  Madeline M Farley⁴  Michael Siu⁵  Zora Modrusan⁶  Jeffrey Eastham-Anderson⁷ 

[1] Laboratory of Brain Development and Repair, The Rockefeller University, New York, United States;Bioinformatics, Genentech, Inc., San Francisco, United States;Department of Neuroscience, Genentech, Inc., San Francisco, United States;Department of Neurosurgery, Baylor College of Medicine, Houston, Texas;Discovery Chemistry, Genentech, Inc., San Francisco, United States;Molecular Biology, Genentech, Inc., San Francisco, United States;Pathology, Genentech, Inc., San Francisco, United States;

关键词: optic nerve;    unfolded protein response;    apoptosis;    neurodegeneration;    axonal injury;    stress response;   

DOI  :  10.7554/eLife.20725

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown