Jong Youl Kim1, Nuri Kim1, Zhen Zheng1, Jong Eun Lee1, Midori A Yenari2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND AND PURPOSE: 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 (Hsp70transgenic 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. METHODS:Mice were subjected to distal middle cerebral artery occlusion. Neuro-2a cells were subjected to oxygenglucose deprivation. Hsp70transgenic 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. RESULTS:Hsp70transgenic 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 oxygenglucose deprivation, while downregulating dynamin and Fas expression. Further, dynamin inhibition was found to be neuroprotective. CONCLUSIONS: 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.
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