Cellular Functions of the Prion Protein

朊病毒病是人类和动物致命的神经退行性疾病。大量证据表明，这些疾病的中心分子事件是PrPC（一种正常的细胞表面糖蛋白）向PrPSc（一种在缺乏核酸的情况下具有传染性的异常异构体）的构象转化。尽管我们现在已经详细了解了PrPSc在疾病过程中的作用，但PrPC的正常生物学功能仍然是一个谜。这项资助的主要目的是研究一个令人兴奋的关于PrPC生理功能的新假设。我们认为PrPC在保护细胞免受促凋亡应激中起关键作用，而这种细胞保护活性的破坏会导致神经退行性变。首先，除了蛋白质组学技术外，我们将利用酵母中新颖的基于基因的筛选来鉴定在PrP的细胞保护和细胞毒性作用中起作用的相互作用蛋白。接下来，我们将使用各种生化和细胞为基础的方法来研究PrPC细胞保护作用的机制。最后，我们将利用转基因小鼠分析Bax在PrPSc和其他异常形式PrP的神经毒性作用中的作用。除了阐明PrPC的正常功能外，我们的发现很可能为朊病毒引起神经变性的机制提供见解，并将为如何阻断这一过程作为治疗策略提供线索。这里发现的prp相互作用蛋白和细胞通路也可能与其他神经退行性疾病有关，如阿尔茨海默病、帕金森病和亨廷顿病，在这些疾病中细胞应激起着突出作用。

Prion diseases are fatal neurodegenerative disorders of humans and animals. A wealth of evidence suggests that the central molecular event in these diseases is the conformational conversion of PrPC, a normal cell-surface glycoprotein, into PrPSc, an abnormal isoform that is infectious in the absence of nucleic acid. Although we now have a detailed picture of how PrPSc figures in the disease process, the normal biological function of PrPC has remained a mystery. The major objective of this grant is to investigate an exciting new hypothesis concerning the physiological function of PrPC. We propose that PrPC plays a key role in protection of cells from pro-apoptotic stresses, and that subversion of this cytoprotective activity causes neurodegeneration. First, we will utilize novel, genetically-based screens in yeast, in addition to proteomics technologies, to identify interacting proteins that play a role in the cytoprotective and cytotoxic actions of PrP. Next, we will investigate the mechanisms underlying the cytoprotective effects of PrPC using a variety of biochemical and cell-based approaches. Finally, we will utilize transgenic mice to analyze the role of Bax in the neurotoxic actions of PrPSc and other abnormal forms of PrP. In addition to elucidating the normal function of PrPC, our findings are likely to provide insights into the mechanisms by which prions cause neurodegeneration, and will yield clues as to how this process can be blocked as a therapeutic strategy. The PrP-interacting proteins and cellular pathways identified here may also be relevant to other neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases, in which cellular stress plays a prominent role.