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A human prion protein peptide (PrP59–91) protects against copper neurotoxicity

Abstract

Human cellular prion protein (PrPC) is involved in several neurodegenerative disorders; however, its normal function is unknown. We report here that a synthetic peptide corresponding to the four-octarepeat sequence of the PrPC (PrP59–91) protects hippocampal neurons against copper neurotoxic effects in vivo. Using a rat bilateral intrahippocampal injection model, we found that PrP59–91 protects against copper-induced neurotoxicity, including a recovery in spatial learning performance and a reduced neuronal cell loss and astrogliosis. Previous studies from our laboratory indicated that a tryptophan (Trp) residue plays a key role in the reduction of copper(II) to copper(I); therefore several PrP59–91 fragments lacking histidine (His) and Trp residues were tested for their capacity to protect from copper toxicity. A PrP59–91 peptide lacking His residue shows as much neuroprotection as the native peptide; however, PrP59–91 without Trp residues only partially protected against copper toxicity. The neuroprotective effect not only occurs with PrP59–91, in fact a full neuroprotection was also observed using just one octamer of the N-terminal region of prion protein. We conclude that the N-terminal tandem octarepeat of the human PrPC protects neurons against copper toxicity by a differential contribution of the binding (His) and reducing (Trp) copper activities of PrP59–91. Our results are consistent with the idea that PrPC function is related to copper homeostasis.

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Acknowledgements

This work was supported by the International Copper Association (ICA, New York, NY), FONDAP-Biomedicine Grant No. 13980001 and the Millennium Institute of Fundamental and Applied Biology (MIFAB).

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Correspondence to N C Inestrosa.

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Chacón, M., Barría, M., Lorca, R. et al. A human prion protein peptide (PrP59–91) protects against copper neurotoxicity. Mol Psychiatry 8, 853–862 (2003). https://doi.org/10.1038/sj.mp.4001400

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