Journal
NEUROSCIENCE LETTERS
Volume 469, Issue 1, Pages 122-126Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2009.11.057
Keywords
Vitamin E; Tocopherol; Prion; Protein kinase C; Rapamycin; mTOR
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Funding
- DFG [GRK1033]
- BMBF, Germany
- EU [FP6 2004 Food 3B 023183]
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Beneficial effects of tocopherols, or vitamin E, on degenerative brain conditions have been attributed mainly to their antioxidant effects. Non-antioxidant effects of the tocopherols have been shown to be mediated by inhibition of protein kinase C (PKC) signaling. Prion disease is a paradigmatic protein conformational disease characterized by the induced conversion of a normal host protein PrPC to adopt a pathogenic conformation PrPSc. The molecular regulation of prion replication is poorly understood. Here, we show that tocopherols inhibit prion replication by a structure-activity relationship for antiprion activity independent of antioxidant activity with tocopherol succinate (TS) posessing highest EC50 at 7 mu M. Only TS but not an equally antiprion active PKC inhibitor could be partially antagonized by substochiometric 1 nM rapamycin suggesting that there are pathways via mammalian target of rapamycin (mTOR) that interfere with tocopherol's biological effects. Interaction with the mTOR pathway is a yet undescribed characteristic of tocopherol derivatives, potentially significant for pathophysiological processes other than prion propagation. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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