Overexpression of PrPCby Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model
| Autor: | Shinn Zong Lin, Hui I. Yang, Kuo Wei Li, Woei Cherng Shyu, Dah-Ching Ding, Ming Fu Chiang, Hung Li, Shih Fen Chen |
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| Rok vydání: | 2005 |
| Předmět: |
Male
animal diseases Genetic Vectors Ischemia Apoptosis Biology Nervous System Neuroprotection Adenoviridae Brain Ischemia Rats Sprague-Dawley Downregulation and upregulation Neurobiology of Disease mental disorders Gene expression medicine Animals Humans PrPC Proteins Tissue Distribution Extracellular Signal-Regulated MAP Kinases Hypoxia Cells Cultured Cerebral Cortex Kinase General Neuroscience Brain Cerebral Infarction Transfection medicine.disease Molecular biology Rats nervous system diseases Cell biology Oxygen Stroke Disease Models Animal Neuroprotective Agents Cell culture Gene Targeting Signal transduction Signal Transduction |
| Zdroj: | The Journal of Neuroscience. 25:8967-8977 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Prion diseases are induced by pathologically misfolded prion protein (PrPSc), which recruit normal sialoglycoprotein PrPCby a template-directed process. In this study, we investigated the expression of PrPCin 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 PrPCprotein expression increased in ischemic brain tissue in a time-dependent manner. In addition, PrPCprotein expression was seen to colocalize with neuron, glial, and vascular endothelial cells in the penumbric region of the ischemic brain. Overexpression of PrPCby 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 PrPCin the neuroprotective adaptive cellular response to ischemic lesions. Concomitant upregulation of PrPCand 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 PrPCpromoter 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 PrPCresulting in gene expression of the prion gene. In summary, we conclude that upregulation of PrPCexpression after cerebral ischemia and hypoxia exerts a neuroprotective effect on injured neural tissue. This study suggests that PrPChas physiological relevance to cerebral ischemic injury and could be useful as a therapeutic target for the treatment of cerebral ischemia. |
| Databáze: | OpenAIRE |
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