Chacón M A, Barría M I, Lorca R, Huidobro-Toro J P, Inestrosa N C
Centro de Regulación Celular y Patología 'Dr Joaquín V Luco', MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Mol Psychiatry. 2003 Oct;8(10):853-62, 835. doi: 10.1038/sj.mp.4001400.
Human cellular prion protein (PrP(C)) 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 PrP(C) (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 PrP(C) 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 PrP(C) function is related to copper homeostasis.
人类细胞朊蛋白（PrP(C)）与多种神经退行性疾病有关；然而，其正常功能尚不清楚。我们在此报告，一种与PrP(C)的四聚八肽重复序列相对应的合成肽（PrP(59-91)）在体内可保护海马神经元免受铜的神经毒性作用。使用大鼠双侧海马内注射模型，我们发现PrP(59-91)可防止铜诱导的神经毒性，包括空间学习能力的恢复以及神经元细胞损失和星形胶质细胞增生的减少。我们实验室先前的研究表明，色氨酸（Trp）残基在将铜（II）还原为铜（I）的过程中起关键作用；因此，对几个缺乏组氨酸（His）和Trp残基的PrP(59-91)片段进行了测试，以评估它们保护细胞免受铜毒性的能力。缺乏His残基的PrP(59-91)肽显示出与天然肽一样多的神经保护作用；然而，没有Trp残基的PrP(59-91)仅部分保护细胞免受铜毒性。神经保护作用不仅发生在PrP(59-91)上，实际上，仅使用朊蛋白N端区域的一个八聚体也观察到了完全的神经保护作用。我们得出结论，人类PrP(C)的N端串联八肽重复序列通过PrP(59-91)结合（His）和还原（Trp）铜的活性的不同贡献来保护神经元免受铜毒性。我们的结果与PrP(C)功能与铜稳态相关的观点一致。
