Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.
Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Sci Rep. 2017 Mar 23;7:44723. doi: 10.1038/srep44723.
Prion diseases are fatal neurodegenerative disorders affecting several mammalian species, characterized by the accumulation of the misfolded form of the prion protein, which is followed by the induction of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). GRP78, also called BiP, is a master regulator of the UPR, reducing ER stress levels and apoptosis due to an enhancement of the cellular folding capacity. Here, we studied the role of GRP78 in prion diseases using several in vivo and in vitro approaches. Our results show that a reduction in the expression of this molecular chaperone accelerates prion pathogenesis in vivo. In addition, we observed that prion replication in cell culture was inversely related to the levels of expression of GRP78 and that both proteins interact in the cellular context. Finally, incubation of PrP with recombinant GRP78 led to the dose-dependent reduction of protease-resistant PrP in vitro. Our results uncover a novel role of GRP78 in reducing prion pathogenesis, suggesting that modulating its levels/activity may offer a novel opportunity for designing therapeutic approaches for these diseases. These findings may also have implications for other diseases involving the accumulation of misfolded proteins.
朊病毒病是一种致命的神经退行性疾病，影响多种哺乳动物物种，其特征是错误折叠的朊病毒蛋白积累，随后引发内质网（ER）应激和未折叠蛋白反应（UPR）的激活。GRP78，也称为 BiP，是 UPR 的主要调节剂，通过增强细胞折叠能力来降低 ER 应激水平和细胞凋亡。在这里，我们使用几种体内和体外方法研究了 GRP78 在朊病毒病中的作用。我们的结果表明，这种分子伴侣表达的减少会加速体内朊病毒病的发病机制。此外，我们观察到细胞培养中的朊病毒复制与 GRP78 的表达水平呈反比，并且这两种蛋白质在细胞环境中相互作用。最后，用重组 GRP78 孵育 PrP 会导致体外蛋白酶抗性 PrP 的剂量依赖性减少。我们的研究结果揭示了 GRP78 在降低朊病毒病发病机制中的新作用，表明调节其水平/活性可能为这些疾病的治疗方法设计提供新的机会。这些发现也可能对涉及错误折叠蛋白积累的其他疾病产生影响。
