In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 25, No. 39 ( 2005-09-28), p. 8967-8977
Abstract:
Prion diseases are induced by pathologically misfolded prion protein (PrP Sc ), which recruit normal sialoglycoprotein PrP C by a template-directed process. In this study, we investigated the expression of PrP C in a rat model of cerebral ischemia to more fully understand its physiological role. Immunohistochemical analysis demonstrated that PrP C -immunoreactive cells increased significantly in the penumbra of ischemic rat brain compared with the untreated brain. Western blot analysis showed that PrP C protein expression increased in ischemic brain tissue in a time-dependent manner. In addition, PrP C protein expression was seen to colocalize with neuron, glial, and vascular endothelial cells in the penumbric region of the ischemic brain. Overexpression of PrP C by injection of rAd (replication-defective recombinant adenoviral)-PGK (phosphoglycerate kinase)-PrP C -Flag into ischemic rat brain improved neurological behavior and reduced the volume of cerebral infarction, which is supportive of a role for PrP C in the neuroprotective adaptive cellular response to ischemic lesions. Concomitant upregulation of PrP C 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 PrP C 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 PrP C resulting in gene expression of the prion gene. In summary, we conclude that upregulation of PrP C expression after cerebral ischemia and hypoxia exerts a neuroprotective effect on injured neural tissue. This study suggests that PrP C has physiological relevance to cerebral ischemic injury and could be useful as a therapeutic target for the treatment of cerebral ischemia.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.1115-05.2005
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2005
detail.hit.zdb_id:
1475274-8
SSG:
12
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