Mizuno Dai, Koyama Hironari, Ohkawara Susumu, Sadakane Yutaka, Kawahara Masahiro
Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
Curr Pharm Biotechnol. 2014;15(11):1049-57. doi: 10.2174/1389201015666141103020625.
Prion diseases are progressive neurodegenerative diseases that are associated with conformational changes that convert normal cellular prion protein (PrP(C)) into an abnormal pathogenic prion protein (PrP(Sc)). It is widely recognized that prion diseases are forms of transmissible amyloidosis and are considered to be protein-misfolding diseases (conformational diseases), a category that also includes Alzheimer's disease. Trace elements play crucial roles in the conformational change affecting PrP(C), and increasing evidence suggests that PrP(C) is a metal-binding protein that is involved in the homeostasis of Cu, Zn, and Fe. In this article, we review the current understanding of links between trace elements and the conformational change to PrP(Sc), based on our studies using synthetic prion peptides, as well as other new findings. We also focus on PrP(Sc)-induced disruption of Ca homeostasis as a molecular mechanism for neurodegeneration in prion diseases. Possible roles of carnosine (ß-alanyl histidine) as a candidate neuroprotective substance use in prion diseases are also discussed.
朊病毒疾病是进行性神经退行性疾病，与构象变化有关，这种构象变化将正常细胞朊病毒蛋白（PrP(C)）转化为异常致病性朊病毒蛋白（PrP(Sc)）。人们普遍认为朊病毒疾病是可传播淀粉样变性的形式，被认为是蛋白质错误折叠疾病（构象疾病），这一类别还包括阿尔茨海默病。微量元素在影响PrP(C)的构象变化中起关键作用，越来越多的证据表明PrP(C)是一种金属结合蛋白，参与铜、锌和铁的体内平衡。在本文中，我们基于使用合成朊病毒肽的研究以及其他新发现，综述了目前对微量元素与PrP(Sc)构象变化之间联系的理解。我们还关注PrP(Sc)诱导的钙稳态破坏，将其作为朊病毒疾病神经退行性变的分子机制。还讨论了肌肽（β-丙氨酰组氨酸）作为朊病毒疾病中候选神经保护物质的可能作用。
