Interaction of metals with prion protein: Possible role of divalent cations in the pathogenesis of Prion diseases
Interaction of metals with prion protein: Possible role of divalent cations in the pathogenesis of Prion diseases
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DOI：
10.1016/j.neuro.2006.06.004
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发表时间：
2006-09-01
期刊：
影响因子：
3.4
通讯作者：
Kanthasamy, Anumantha G.
中科院分区：
文献类型：
--
作者：
Choi, Christopher J.;Kanthasamy, Arthi;Kanthasamy, Anumantha G.
朊病毒病是一种致命的神经退行性疾病，影响人类和动物。快速的临床进展，蛋白质构象的变化，跨物种传播和大规模神经元变性是这种破坏性退行性疾病的一些关键特征。虽然病因不明，但细胞朊病毒蛋白的异常加工在朊病毒疾病的发病机制中已得到充分证实。正常细胞朊蛋白（PrPc）在哺乳动物中高度保守，主要在脑中表达。然而，正常朊病毒蛋白在中枢神经系统中的确切功能尚未完全阐明。朊病毒蛋白可以作为金属结合蛋白，因为二价阳离子如铜、锌和锰可以结合PrPc的N-末端的八肽重复序列。由于这些金属与八肽的结合已经被提出影响朊病毒蛋白的结构和功能特性，因此过渡金属水平的改变可以改变疾病的进程。此外，细胞的抗氧化能力显着受损，由于正常的朊病毒蛋白（PrPc）的转换为一个异常的羊瘙痒症朊病毒（PrPc）蛋白，这表明氧化应激可能在朊病毒疾病的神经退行性过程中发挥作用。细胞过渡金属失衡和氧化应激增加的组合可能进一步加剧PrPsc的神经毒性作用。本文综述了朊病毒蛋白的结构和功能，以及铜、锰、铁等金属在朊病毒蛋白生理功能中的作用，并探讨了过渡金属在朊病毒病发病机制中的可能作用。(C)2006年爱思唯尔公司All rights reserved.
Prion diseases are fatal neurodegenerative disorders that affect both humans and animals. The rapid clinical progression, change in protein conformation, cross-species transmission and massive neuronal degeneration are some key features of this devastating degenerative condition. Although the etiology is unknown, aberrant processing of cellular prion proteins is well established in the pathogenesis of prion diseases. Normal cellular prion protein (PrPc) is highly conserved in mammals and expressed predominantly in the brain. Nevertheless, the exact function of the normal prion protein in the CNS has not been fully elucidated. Prion proteins may function as a metal binding protein because divalent cations such as copper, zinc and manganese can bind to octapeptide repeat sequences in the N-terminus of PrPc. Since the binding of these metals to the octapeptide has been proposed to influence both structural and functional properties of prion proteins, alterations in transition metal levels can alter the course of the disease. Furthermore, cellular antioxidant capacity is significantly compromised due to conversion of the normal prion protein (PrPc) to an abnormal scrapie prion (PrPc) protein, suggesting that oxidative stress may play a role in the neurodegenerative process of prion diseases. The combination of imbalances in cellular transition metals and increased oxidative stress could further exacerbate the neurotoxic effect of PrPsc. This review includes an overview of the structure and function of prion proteins, followed by the role of metals such as copper, manganese and iron in the physiological function of the PrPc, and the possible role of transition metals in the pathogenesis of the prion disease. (C) 2006 Elsevier Inc. All rights reserved.