Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury.
Chaperones, especially the stress inducible Hsp70, have been studied for their potential to protect the brain from ischemic injury. While they protect from both global and focal ischemia in vivo and cell culture models of ischemia/reperfusion injury in vitro, the mechanism of protection is not well understood. Protein aggregation is part of the etiology of chronic neurodegenerative diseases such as Huntington's and Alzheimer's, and recent data demonstrate protein aggregates in animal models of stroke. We now demonstrate that overexpression of Hsp70 in hippocampal CA1 neurons reduces evidence of protein aggregation under conditions where neuronal survival is increased. We have also demonstrated protection by the cochaperone Hdj-2 in vitro and demonstrated that this is associated with reduced protein aggregation identified by ubiquitin immunostaining. Hdj-2 can prevent protein aggregate formation by itself, but can only facilitate protein folding in conjunction with Hsp70. Pharmacological induction of Hsp70 was found to reduce both apoptotic and necrotic astrocyte death induced by glucose deprivation or oxygen glucose deprivation. Protection from ischemia and ischemia-like injury by chaperones thus involves at least anti-apoptotic, anti-necrotic and anti-protein aggregation mechanisms.
Giffard
Rona G
RG
Department of Anesthesia, Stanford University, Stanford, CA 94305, USA. rona.giffard@stanford.edu
Xu
Lijun
L
Zhao
Heng
H
Carrico
Whitney
W
Ouyang
Yibing
Y
Qiao
Yanli
Y
Sapolsky
Robert
R
Steinberg
Gary
G
Hu
Bingren
B
Yenari
Midori A
MA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D016227:Benzoquinones; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic; D051379:Mice; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism*; D017510:Protein Folding; D011809:Quinones / Q000378:metabolism; D051381:Rats; D025801:Ubiquitin
D016227:Benzoquinones; D002352:Carrier Proteins; C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D011809:Quinones; D025801:Ubiquitin; D005947:Glucose; C001277:geldanamycin