NR APGB
AU Chacon,M.A.; Barria,M.I.; Lorca,R.A.; Huidobro-Toro,J.P.; Inestrosa,N.C.
TI A human prion protein peptide (PrP(59-91)) protects against copper neurotoxicity
QU Molecular Psychiatry 2003 Oct; 8(10): 853-62, 835
PT journal article
AB 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 (PrP(59-91)) protects hippocampal neurons against copper neurotoxic effects in vivo. Using a rat bilateral intrahippocampal injection model, we found that PrP(59-91) 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 PrP(59-91) fragments lacking histidine (His) and Trp residues were tested for their capacity to protect from copper toxicity. A PrP(59-91) peptide lacking His residue shows as much neuroprotection as the native peptide; however, PrP(59-91) without Trp residues only partially protected against copper toxicity. The neuroprotective effect not only occurs with PrP(59-91), 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 PrP(59-91). Our results are consistent with the idea that PrPc function is related to copper homeostasis.
MH Amino Acid Sequence; Animals; Astrocytes/drug effects/pathology; Copper/*toxicity; Hippocampus/drug effects/pathology/physiology; Injections, Intraventricular; Male; Maze Learning/drug effects; Memory/*drug effects; Molecular Sequence Data; Neurotoxins/pharmacology; Peptide Fragments/chemistry/*pharmacology; Prions/chemistry/*pharmacology; Rats; Rats, Sprague-Dawley; Space Perception/*drug effects; Support, Non-U.S. Gov't
AD Centro de Regulacion Celular y Patologia 'Dr Joaquin V Luco', MIFAB, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile.
SP englisch
PO England