PMID- 19889624
OWN - NLM
STAT- MEDLINE
DCOM- 20100126
LR  - 20240322
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 2
DP  - 2010 Jan 8
TI  - Interaction of double-stranded RNA-dependent protein kinase (PKR) with the death 
      receptor signaling pathway in amyloid beta (Abeta)-treated cells and in APPSLPS1 
      knock-in mice.
PG  - 1272-82
LID - 10.1074/jbc.M109.041954 [doi]
AB  - For 10 years, research has focused on signaling pathways controlling translation 
      to explain neuronal death in Alzheimer Disease (AD). Previous studies 
      demonstrated in different cellular and animal models and AD patients that 
      translation is down-regulated by the activation of double-stranded RNA-dependent 
      protein kinase (PKR). Among downstream factors of PKR, the Fas-associated protein 
      with a death domain (FADD) and subsequent activated caspase-8 are responsible for 
      PKR-induced apoptosis in recombinant virus-infected cells. However, no studies 
      have reported the role of PKR in death receptor signaling in AD. The aim of this 
      project is to determine physical and functional interactions of PKR with FADD in 
      amyloid-beta peptide (Abeta) neurotoxicity and in APP(SL)PS1 KI transgenic mice. 
      In SH-SY5Y cells, results showed that Abeta42 induced a large increase in 
      phosphorylated PKR and FADD levels and a physical interaction between PKR and 
      FADD in the nucleus, also observed in the cortex of APP(SL)PS1 KI mice. However, 
      PKR gene silencing or treatment with a specific PKR inhibitor significantly 
      prevented the increase in pT(451)-PKR and pS(194)-FADD levels in SH-SY5Y nuclei 
      and completely inhibited activities of caspase-3 and -8. The contribution of PKR 
      in neurodegeneration through the death receptor signaling pathway may support the 
      development of therapeutics targeting PKR to limit neuronal death in AD.
FAU - Couturier, Julien
AU  - Couturier J
AD  - Research Group on Brain Aging, GReViC EA 3808, University of Poitiers, 6 rue de 
      la Miletrie, BP 199, 86034 Poitiers Cedex, France.
FAU - Morel, Milena
AU  - Morel M
FAU - Pontcharraud, Raymond
AU  - Pontcharraud R
FAU - Gontier, Virginie
AU  - Gontier V
FAU - Fauconneau, Bernard
AU  - Fauconneau B
FAU - Paccalin, Marc
AU  - Paccalin M
FAU - Page, Guylene
AU  - Page G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091104
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Fadd protein, mouse)
RN  - 0 (Fas-Associated Death Domain Protein)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Casp8 protein, mouse)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 8)
SB  - IM
MH  - Alzheimer Disease/chemically induced/genetics/*metabolism
MH  - Amyloid beta-Peptides/metabolism/*pharmacology
MH  - Animals
MH  - Caspase 3/genetics/metabolism
MH  - Caspase 8/genetics/metabolism
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Cell Nucleus/genetics/metabolism
MH  - Cerebral Cortex/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Fas-Associated Death Domain Protein/genetics/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Phosphorylation/drug effects/genetics
MH  - Signal Transduction/*drug effects/genetics
MH  - eIF-2 Kinase/antagonists & inhibitors/genetics/*metabolism
PMC - PMC2801255
EDAT- 2009/11/06 06:00
MHDA- 2010/01/27 06:00
PMCR- 2011/01/08
CRDT- 2009/11/06 06:00
PHST- 2009/11/06 06:00 [entrez]
PHST- 2009/11/06 06:00 [pubmed]
PHST- 2010/01/27 06:00 [medline]
PHST- 2011/01/08 00:00 [pmc-release]
AID - S0021-9258(20)58883-2 [pii]
AID - M109.041954 [pii]
AID - 10.1074/jbc.M109.041954 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Jan 8;285(2):1272-82. doi: 10.1074/jbc.M109.041954. Epub 2009 
      Nov 4.