Open AccessThe Role of the Octarepeat Region in Neuroprotective Function of the Cellular Prion Protein
Author(s) -
Mitteregger Gerda,
Vosko Milan,
Krebs Bjarne,
Xiang Wei,
Kohlmannsperger Veronika,
Nölting Svenja,
Hamann Gerhard F.,
Kretzschmar Hans A.
Publication year - 2007
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2007.00061.x
Subject(s) - neuroprotection , prnp , knockout mouse , oxidative stress , genetically modified mouse , biology , transgene , pathogenesis , microbiology and biotechnology , wild type , endocrinology , medicine , neuroscience , immunology , receptor , biochemistry , gene , mutant , allele
Structural alterations of the cellular prion protein (PrP C ) seem to be the core of the pathogenesis of prion diseases. However, the physiological function of PrP C remains an enigma. Cell culture experiments have indicated that PrP C 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 PrP C 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 PrP C physiology and neuroprotection against oxidative stress in vivo .