Oxidative injury to the endoplasmic reticulum in mouse brains after transient focal ischemia.
Oxidative damage to the endoplasmic reticulum (ER) could be involved in ischemic neuronal cell death because this organelle is susceptible to reactive oxygen species. Using wild-type mice and copper/zinc-superoxide dismutase (SOD1) transgenic mice, we induced focal cerebral ischemia and compared neuronal degeneration and ER stress, that is, phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and RNA-dependent protein kinase-like ER eIF2alpha kinase (PERK). We found that neurons with severe and prolonged phosphorylation of eIF2alpha and PERK underwent later degeneration, and that this was partially prevented by SOD1 overexpression. Signals for superoxide production and phospho-PERK were colocalized, which further indicates a pivotal role for superoxide in ER damage. We investigated the molecular mechanisms of oxidative ER stress and found that detachment of glucose-regulated protein 78 from PERK was the key step. We conclude that ER damage is involved in oxidative neuronal injury in the brain after ischemia/reperfusion.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Takeshi
T
Hayashi
Atsushi
A
Saito
Shuzo
S
Okuno
Michel
M
Ferrand-Drake
Robert L
RL
Dodd
Pak H
PH
Chan
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004734:Energy Metabolism / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D005947:Glucose; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013481:Superoxides; D019892:eIF-2 Kinase; C000606291:Sod1 protein, mouse