The Role of the Octarepeat Region in Neuroprotective Function of the Cellular Prion Protein

By G. Mitteregger, Milan Vosko, Bjarne Krebs, W. Xiang, Veronika Kohlmannsperger, S. Nölting, Gerhard F. Hamann, Hans A. Kretzschmar. Brain Pathology, 2007

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Structural alterations of the cellular prion protein (PrPC) seem to be the core of the pathogenesis of prion diseases. However, the physiological function of PrPC remains an enigma. Cell culture experiments have indicated that PrPC and in particular its N‐terminal octarepeat region together with the phosphatidylinositol 3‐kinase (PI3K)/Akt signaling pathways have a fundamental involvement in neuroprotection and oxidative stress reactions. We used wild‐type mice, PrP knockout (Prnp−/−) animals and transgenic mice that lack the octarepeat region (C4/−) and subjected them to controlled ischemia. We identified an increased cleavage and synthesis of PrPC in ischemic brain areas of wild‐type mice compared with sham controls. The infarct size in Prnp−/− animals was increased threefold when compared with wild‐type mice. The infarct size in C4/− animals was identical to Prnp−/− mice, that is, around three times larger than in wild‐type mice. We showed that the PrP in C4/− mice does not functionally rescue the Prnp−/− phenotype; furthermore it is unable to undergo β cleavage, although an increased amount of C1 fragments was found in ischemic brain areas compared with sham controls. We demonstrated that the N‐terminal octarepeat region has a lead function in PrPC physiology and neuroprotection against oxidative stress in vivo.

Subfields: Molecular Biology, Neurology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/2943e3c1cfce8ba69458969b43985fcaba86d2c7

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