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The Journal of Neuroscience, September 28, 2005, 25(39):8967-8977; doi:10.1523/JNEUROSCI.1115-05.2005
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Neurobiology of Disease
Overexpression of PrPC by Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model
Woei-Cherng Shyu,1 * Shinn-Zong Lin,1 * Ming-Fu Chiang,2 Dah-Ching Ding,1 Kuo-Wei Li,1 Shih-Fen Chen,1 Hui-I Yang,1 andHung Li3,4 1Department of Neurology, Neuro-Medical Scientific Center, Tzu-Chi Buddhist General Hospital, Tzu-Chi University, Hualien, Taiwan 970, 2Department of Neurosurgery, Mackay Memorial Hospital, Mackay Junior College of Nursing, Taipei, Taiwan 112, 3Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 115, and 4Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan 112
Prion diseases are induced by pathologically misfolded prion protein (PrPSc), which recruit normal sialoglycoprotein PrPC by a template-directed process. In this study, we investigated the expression of PrPC in a rat model of cerebral ischemia to more fully understand its physiological role. Immunohistochemical analysis demonstrated that PrPC-immunoreactive cells increased significantly in the penumbra of ischemic rat brain compared with the untreated brain. Western blot analysis showed that PrPC protein expression increased in ischemic brain tissue in a time-dependent manner. In addition, PrPC protein expression was seen to colocalize with neuron, glial, and vascular endothelial cells in the penumbric region of the ischemic brain. Overexpression of PrPC by injection of rAd (replication-defective recombinant adenoviral)-PGK (phosphoglycerate kinase)-PrPC-Flag into ischemic rat brain improved neurological behavior and reduced the volume of cerebral infarction, which is supportive of a role for PrPC in the neuroprotective adaptive cellular response to ischemic lesions. Concomitant upregulation of PrPC and activated extracellular signal-regulated kinase (ERK1/2) under hypoxia–reoxygenation in primary cortical cultures was shown to be dependent on ERK1/2 phosphorylation. During hypoxia–reoxygenation, mouse neuroblastoma cell line N18 cells transfected with luciferase rat PrPC promoter reporter constructs, containing the heat shock element (HSE), expressed higher luciferase activities (3- to 10-fold) than those cells transfected with constructs not containing HSE. We propose that HSTF-1 (hypoxia-activated transcription factor), phosphorylated by ERK1/2, may in turn interact with HSE in the promoter of PrPC resulting in gene expression of the prion gene. In summary, we conclude that upregulation of PrPC expression after cerebral ischemia and hypoxia exerts a neuroprotective effect on injured neural tissue. This study suggests that PrPC has physiological relevance to cerebral ischemic injury and could be useful as a therapeutic target for the treatment of cerebral ischemia.
Key words: prion protein (PrPC); stress protein; cerebral ischemia animal model; hypoxia–reoxygenation; primary cortical neurons; neuroprotection
Received Dec 20, 2004; revised June 10, 2005; accepted August 2, 2005.
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