Iwamaru Yoshifumi, Shimizu Yoshihisa, Imamura Morikazu, Murayama Yuichi, Endo Ryo, Tagawa Yuichi, Ushiki-Kaku Yuko, Takenouchi Takato, Kitani Hiroshi, Mohri Shirou, Yokoyama Takashi, Okada Hiroyuki
Prion Disease Research Center, National Institute of Animal Health, Ibaraki, Japan.
J Neurochem. 2008 Nov;107(3):636-46. doi: 10.1111/j.1471-4159.2008.05628.x. Epub 2008 Sep 20.
Prion diseases are fatal neurodegenerative disorders, and the conformational conversion of normal cellular prion protein (PrP(C)) into its pathogenic, amyloidogenic isoform (PrP(Sc)) is the essential event in the pathogenesis of these diseases. Lactoferrin (LF) is a cationic iron-binding glycoprotein belonging to the transferrin (TF) family, which accumulates in the amyloid deposits in the brain in neurodegenerative disorders, such as Alzheimer's disease and Pick's disease. In the present study, we have examined the effects of LF on PrP(Sc) formation by using cell culture models. Bovine LF inhibited PrP(Sc) accumulation in scrapie-infected cells in a time- and dose-dependent manner, whereas TF was not inhibitory. Bioassays of LF-treated cells demonstrated prolonged incubation periods compared with non-treated cells indicating a reduction of prion infectivity. LF mediated the cell surface retention of PrP(C) by diminishing its internalization and was capable of interacting with PrP(C) in addition to PrP(Sc). Furthermore, LF partially inhibited the formation of protease-resistant PrP as determined by the protein misfolding cyclic amplification assay. Our results suggest that LF has multifunctional antiprion activities.
朊病毒疾病是致命的神经退行性疾病，正常细胞朊病毒蛋白（PrP(C)）向其致病性淀粉样异构体（PrP(Sc)）的构象转变是这些疾病发病机制中的关键事件。乳铁蛋白（LF）是一种属于转铁蛋白（TF）家族的阳离子铁结合糖蛋白，在神经退行性疾病如阿尔茨海默病和匹克氏病中，它会在大脑的淀粉样沉积物中积累。在本研究中，我们使用细胞培养模型研究了LF对PrP(Sc)形成的影响。牛乳铁蛋白以时间和剂量依赖性方式抑制瘙痒病感染细胞中PrP(Sc)的积累，而转铁蛋白则没有抑制作用。对经LF处理的细胞进行生物测定表明，与未处理的细胞相比，潜伏期延长，表明朊病毒感染性降低。LF通过减少PrP(C)的内化介导其在细胞表面的保留，并且除了PrP(Sc)之外还能够与PrP(C)相互作用。此外，通过蛋白质错误折叠循环扩增试验确定，LF部分抑制了蛋白酶抗性PrP的形成。我们的结果表明，LF具有多功能抗朊病毒活性。
