PMID- 28440222
OWN - NLM
STAT- MEDLINE
DCOM- 20180105
LR  - 20181113
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 6
DP  - 2017 Apr 25
TI  - Dual leucine zipper kinase-dependent PERK activation contributes to neuronal 
      degeneration following insult.
LID - e20725 [pii]
LID - 10.7554/eLife.20725 [doi]
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.
FAU - Larhammar, Martin
AU  - Larhammar M
AUID- ORCID: 0000-0002-1547-6760
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
FAU - Huntwork-Rodriguez, Sarah
AU  - Huntwork-Rodriguez S
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
FAU - Jiang, Zhiyu
AU  - Jiang Z
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
FAU - Solanoy, Hilda
AU  - Solanoy H
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
FAU - Sengupta Ghosh, Arundhati
AU  - Sengupta Ghosh A
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
FAU - Wang, Bei
AU  - Wang B
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
FAU - Kaminker, Joshua S
AU  - Kaminker JS
AD  - Bioinformatics, Genentech, Inc., San Francisco, United States.
FAU - Huang, Kevin
AU  - Huang K
AD  - Bioinformatics, Genentech, Inc., San Francisco, United States.
FAU - Eastham-Anderson, Jeffrey
AU  - Eastham-Anderson J
AD  - Pathology, Genentech, Inc., San Francisco, United States.
FAU - Siu, Michael
AU  - Siu M
AD  - Discovery Chemistry, Genentech, Inc., San Francisco, United States.
FAU - Modrusan, Zora
AU  - Modrusan Z
AD  - Molecular Biology, Genentech, Inc., San Francisco, United States.
FAU - Farley, Madeline M
AU  - Farley MM
AD  - Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.
FAU - Tessier-Lavigne, Marc
AU  - Tessier-Lavigne M
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
AD  - Laboratory of Brain Development and Repair, The Rockefeller University, New York, 
      United States.
FAU - Lewcock, Joseph W
AU  - Lewcock JW
AUID- ORCID: 0000-0003-3012-7881
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
FAU - Watkins, Trent A
AU  - Watkins TA
AUID- ORCID: 0000-0001-6723-3712
AD  - Department of Neuroscience, Genentech, Inc., San Francisco, United States.
AD  - Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.
AD  - OMNI Biomarkers Development, Genentech, Inc., San Francisco, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170425
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (mitogen-activated protein kinase kinase kinase 12)
SB  - IM
MH  - Animals
MH  - Gene Expression Regulation
MH  - MAP Kinase Kinase Kinases/*metabolism
MH  - MAP Kinase Signaling System
MH  - Mice
MH  - *Nerve Degeneration
MH  - Neurons/*enzymology/metabolism
MH  - eIF-2 Kinase/*metabolism
PMC - PMC5404924
OTO - NOTNLM
OT  - apoptosis
OT  - axonal injury
OT  - cell biology
OT  - mouse
OT  - neurodegeneration
OT  - neuroscience
OT  - optic nerve
OT  - stress response
OT  - unfolded protein response
COIS- ML: Employed by Genentech. SH-R: Employed by Genentech at time of study and own 
      shares. ZJ: Employed by Genentech and own shares. HS: Employed by Genentech at 
      time of study and own shares. JSK: Employed by Genentech and own shares. KH: 
      Employed by Genentech at the time of the study. JE-A: Employed by Genentech and 
      own shares. MS: Employed by Genentech and own shares. ZM: Employed by Genentech 
      and own shares. MT-L: Employed by Genentech at time of study. TAW: Employed by 
      Genentech at time of study. The other authors declare that no competing interests 
      exist.
EDAT- 2017/04/26 06:00
MHDA- 2018/01/06 06:00
PMCR- 2017/04/26
CRDT- 2017/04/26 06:00
PHST- 2016/08/16 00:00 [received]
PHST- 2017/03/20 00:00 [accepted]
PHST- 2017/04/26 06:00 [entrez]
PHST- 2017/04/26 06:00 [pubmed]
PHST- 2018/01/06 06:00 [medline]
PHST- 2017/04/26 00:00 [pmc-release]
AID - e20725 [pii]
AID - 20725 [pii]
AID - 10.7554/eLife.20725 [doi]
PST - epublish
SO  - Elife. 2017 Apr 25;6:e20725. doi: 10.7554/eLife.20725.