DOI: 10.1523/jneurosci.1115-05.2005. Overexpression of PrP<sup>C</sup>by Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model

Overexpression of PrPCby Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model

10.1523/jneurosci.1115-05.2005

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

Abstract

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.

Bibliography

Shyu, W.-C., Lin, S.-Z., Chiang, M.-F., Ding, D.-C., Li, K.-W., Chen, S.-F., Yang, H.-I., & Li, H. (2005). Overexpression of PrPCby Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model. The Journal of Neuroscience, 25(39), 8967â8977.

Authors 8

Woei-Cherng Shyu (first)
Shinn-Zong Lin (additional)
Ming-Fu Chiang (additional)
Dah-Ching Ding (additional)
Kuo-Wei Li (additional)
Shih-Fen Chen (additional)
Hui-I Yang (additional)
Hung Li (additional)

References 54 Referenced 103

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Dates

Type	When
Created	19 years, 11 months ago (Sept. 28, 2005, 1:02 p.m.)
Deposited	2 years, 4 months ago (April 13, 2023, 12:59 p.m.)
Indexed	1 day, 4 hours ago (Aug. 29, 2025, 6:43 a.m.)
Issued	19 years, 11 months ago (Sept. 28, 2005)
Published	19 years, 11 months ago (Sept. 28, 2005)
Published Online	19 years, 11 months ago (Sept. 28, 2005)
Published Print	19 years, 11 months ago (Sept. 28, 2005)

Funders 0

None

BibTeX

@article{Shyu_2005, title={Overexpression of PrPCby Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model}, volume={25}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.1115-05.2005}, DOI={10.1523/jneurosci.1115-05.2005}, number={39}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Shyu, Woei-Cherng and Lin, Shinn-Zong and Chiang, Ming-Fu and Ding, Dah-Ching and Li, Kuo-Wei and Chen, Shih-Fen and Yang, Hui-I and Li, Hung}, year={2005}, month=sep, pages={8967–8977} }

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  "abstract": "<jats:p>Prion diseases are induced by pathologically misfolded prion protein (PrP<jats:sup>Sc</jats:sup>), which recruit normal sialoglycoprotein PrP<jats:sup>C</jats:sup>by a template-directed process. In this study, we investigated the expression of PrP<jats:sup>C</jats:sup>in a rat model of cerebral ischemia to more fully understand its physiological role. Immunohistochemical analysis demonstrated that PrP<jats:sup>C</jats:sup>-immunoreactive cells increased significantly in the penumbra of ischemic rat brain compared with the untreated brain. Western blot analysis showed that PrP<jats:sup>C</jats:sup>protein expression increased in ischemic brain tissue in a time-dependent manner. In addition, PrP<jats:sup>C</jats:sup>protein expression was seen to colocalize with neuron, glial, and vascular endothelial cells in the penumbric region of the ischemic brain. Overexpression of PrP<jats:sup>C</jats:sup>by injection of rAd (replication-defective recombinant adenoviral)-PGK (phosphoglycerate kinase)-PrP<jats:sup>C</jats:sup>-Flag into ischemic rat brain improved neurological behavior and reduced the volume of cerebral infarction, which is supportive of a role for PrP<jats:sup>C</jats:sup>in the neuroprotective adaptive cellular response to ischemic lesions. Concomitant upregulation of PrP<jats:sup>C</jats:sup>and activated extracellular signal-regulated kinase (ERK1/2) under hypoxia\u2013reoxygenation in primary cortical cultures was shown to be dependent on ERK1/2 phosphorylation. During hypoxia\u2013reoxygenation, mouse neuroblastoma cell line N18 cells transfected with luciferase rat PrP<jats:sup>C</jats:sup>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<jats:sup>C</jats:sup>resulting in gene expression of the prion gene. In summary, we conclude that upregulation of PrP<jats:sup>C</jats:sup>expression after cerebral ischemia and hypoxia exerts a neuroprotective effect on injured neural tissue. This study suggests that PrP<jats:sup>C</jats:sup>has physiological relevance to cerebral ischemic injury and could be useful as a therapeutic target for the treatment of cerebral ischemia.</jats:p>",
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  "relation": {},
  "ISSN": [
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    "1529-2401"
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  "container-title-short": "J. Neurosci.",
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