Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13733-8. doi: 10.1073/pnas.1211499109. Epub 2012 Aug 6.
Copper influences the pathogenesis of prion disease, but whether it is beneficial or detrimental remains controversial. Copper homeostasis is also essential for normal physiology, as highlighted by the spectrum of diseases caused by disruption of the copper transporting enzymes ATP7A and ATP7B. Here, by using a forward genetics approach in mice, we describe the isolation of three alleles of Atp7a, each with different phenotypic consequences. The mildest of the three, Atp7a(brown), was insufficient to cause lethality in hemizygotes or mottling of the coat in heterozygotes, but did lead to coat hypopigmentation and reduced copper content in the brains of hemizygous males. When challenged with Rocky Mountain Laboratory scrapie, the onset of prion disease was delayed in Atp7a(brown) mice, and significantly less proteinase-resistant prion protein was found in the brains of moribund Atp7a(brown) mice compared with WT littermates. Our results establish that ATP7A-mediated copper homeostasis is important for the formation of pathogenic proteinase-resistant prion protein.
铜会影响朊病毒病的发病机制，但它是有益还是有害仍存在争议。铜稳态对于正常生理也是必不可少的，这一点突出表现在铜转运酶 ATP7A 和 ATP7B 失调引起的一系列疾病中。在这里，我们通过在小鼠中使用正向遗传学方法，描述了 Atp7a 的三种等位基因的分离，每种等位基因都有不同的表型后果。三种等位基因中最温和的 Atp7a(brown) 不足以导致半合子的致死或杂合子时的毛色斑驳，但确实导致了毛色色素沉着减少和半合子雄性大脑中的铜含量降低。当用落基山实验室的瘙痒病进行挑战时，Atp7a(brown) 小鼠的朊病毒病发病时间延迟，与 WT 同窝仔相比，濒死的 Atp7a(brown) 小鼠大脑中的蛋白酶抗性朊病毒蛋白明显减少。我们的结果证实，ATP7A 介导的铜稳态对于形成致病性的蛋白酶抗性朊病毒蛋白很重要。
