title: 70-kDa Heat Shock Protein Downregulates Dynamin in Experimental Stroke: A New Therapeutic Target?
abstract: The 70-kDa heat shock protein (Hsp70) protects brain cells in models of cerebral ischemia. Proteomic screening of mice subjected to middle cerebral artery occlusion identified dynamin as a major downregulated protein in Hsp70-overexpressing mice (Hsp70 transgenic mice). Dynamin-1 is expressed in neurons and participates in neurotransmission, but also transports the death receptor Fas to the cell surface, where it can be bound by its ligand and lead to apoptosis.
  
  
  
  Mice were subjected to distal middle cerebral artery occlusion. Neuro-2a cells were subjected to oxygen glucose deprivation. Hsp70 transgenic and Hsp70-deficient (Hsp70 knockout) mice were compared with wild-type mice for histological and behavioral outcomes. Some mice and neuro-2a cell cultures were given dynasore, a dynamin inhibitor.
  
  
  
  Hsp70 transgenic mice had better outcomes, whereas Hsp70 knockout mice had worse outcomes compared with wild-type mice. This correlated with decreased and increased dynamin expression, respectively. Dynamin colocalized to neurons and Fas, with higher Fas levels and increased caspase-8 expression. Hsp70 induction in neuro-2a cells was protected from oxygen glucose deprivation, while downregulating dynamin and Fas expression. Further, dynamin inhibition was found to be neuroprotective.
  
  
  
  Dynamin may facilitate Fas-mediated apoptotic death in the brain, and Hsp70 may protect by preventing this trafficking. Dynamin should be explored as a new therapeutic target for neuroprotection.
authors.affiliation: From the Department of Neurology, UCSF and the SF Veterans Affairs Medical Center, CA (J.Y.K., N.K., Z.Z., M.A.Y.); and Department of Anatomy, BK21 Plus Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, ROK (J.E.L.).
authors.forename: Jong Youl
authors.initials: JY
authors.lastname: Kim
authors.affiliation: From the Department of Neurology, UCSF and the SF Veterans Affairs Medical Center, CA (J.Y.K., N.K., Z.Z., M.A.Y.); and Department of Anatomy, BK21 Plus Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, ROK (J.E.L.).
authors.forename: Nuri
authors.initials: N
authors.lastname: Kim
authors.affiliation: From the Department of Neurology, UCSF and the SF Veterans Affairs Medical Center, CA (J.Y.K., N.K., Z.Z., M.A.Y.); and Department of Anatomy, BK21 Plus Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, ROK (J.E.L.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: From the Department of Neurology, UCSF and the SF Veterans Affairs Medical Center, CA (J.Y.K., N.K., Z.Z., M.A.Y.); and Department of Anatomy, BK21 Plus Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, ROK (J.E.L.).
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: From the Department of Neurology, UCSF and the SF Veterans Affairs Medical Center, CA (J.Y.K., N.K., Z.Z., M.A.Y.); and Department of Anatomy, BK21 Plus Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, ROK (J.E.L.). yenari@alum.mit.edu.
authors.forename: Midori A
authors.initials: MA
authors.lastname: Yenari
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006835:Hydrazones / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D018840:HSP70 Heat-Shock Proteins; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D019014:fas Receptor; D053181:Caspase 8; D034281:Dynamins
keywords: Fas; apoptosis; dynamin; neuroprotection; stroke