Oxidative damage to the endoplasmic reticulum is implicated in ischemic neuronal cell death.
The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2 alpha (eIF2 alpha) and RNA-dependent protein kinase-like ER eIF2 alpha kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.
Hayashi
Takeshi
T
Department of Neurosurgery and Program in Neurosciences, Stanford University School of Medicine, California 94305, USA.
Saito
Atsushi
A
Okuno
Shuzo
S
Ferrand-Drake
Michel
M
Dodd
Robert L
RL
Nishi
Tatsuro
T
Maier
Carolina M
CM
Kinouchi
Hiroyuki
H
Chan
Pak H
PH
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006360:Heat-Shock Proteins; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D011506:Proteins; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; 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; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011506:Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013481:Superoxides; D019892:eIF-2 Kinase; C051684:GRP78 protein, rat; C000717247:HSPA5 protein, human; C000606290:SOD1 protein, human; C489110:Steroidogenesis-inducing protein, human; C000606292:Sod1 protein, rat