Department of Biochemistry, Boston University School of Medicine, Boston, MA.
Brain Pathol. 2019 Mar;29(2):263-277. doi: 10.1111/bpa.12694. Epub 2019 Jan 17.
Although the mechanisms underlying prion propagation and infectivity are now well established, the processes accounting for prion toxicity and pathogenesis have remained mysterious. These processes are of enormous clinical relevance as they hold the key to identification of new molecular targets for therapeutic intervention. In this review, we will discuss two broad areas of investigation relevant to understanding prion neurotoxicity. The first is the use of in vitro experimental systems that model key events in prion pathogenesis. In this context, we will describe a hippocampal neuronal culture system we developed that reproduces the earliest pathological alterations in synaptic morphology and function in response to PrP . This system has allowed us to define a core synaptotoxic signaling pathway involving the activation of NMDA and AMPA receptors, stimulation of p38 MAPK phosphorylation and collapse of the actin cytoskeleton in dendritic spines. The second area concerns a striking and unexpected phenomenon in which certain structural manipulations of the PrP molecule itself, including introduction of N-terminal deletion mutations or binding of antibodies to C-terminal epitopes, unleash powerful toxic effects in cultured cells and transgenic mice. We will describe our studies of this phenomenon, which led to the recognition that it is related to the induction of large, abnormal ionic currents by the structurally altered PrP molecules. Our results suggest a model in which the flexible N-terminal domain of PrP serves as a toxic effector which is regulated by intramolecular interactions with the globular C-terminal domain. Taken together, these two areas of study have provided important clues to underlying cellular and molecular mechanisms of prion neurotoxicity. Nevertheless, much remains to be done on this next frontier of prion science.
虽然朊病毒传播和感染性的机制现在已经得到很好的证实，但导致朊病毒毒性和发病机制的过程仍然是神秘的。这些过程具有巨大的临床相关性，因为它们是确定新的分子治疗靶点的关键。在这篇综述中，我们将讨论与理解朊病毒神经毒性相关的两个广泛的研究领域。第一个是使用体外实验系统来模拟朊病毒发病机制中的关键事件。在这方面，我们将描述我们开发的一种海马神经元培养系统，该系统复制了对 PrP 反应的突触形态和功能最早的病理改变。该系统使我们能够定义一个核心的突触毒性信号通路，涉及 NMDA 和 AMPA 受体的激活、p38 MAPK 磷酸化的刺激以及树突棘中肌动蛋白细胞骨架的崩溃。第二个领域涉及一个惊人的、出乎意料的现象，即 PrP 分子本身的某些结构操作，包括引入 N 端缺失突变或与 C 端表位结合抗体，会在培养细胞和转基因小鼠中释放出强大的毒性作用。我们将描述我们对这一现象的研究，该研究导致我们认识到，它与结构改变的 PrP 分子诱导大的、异常的离子电流有关。我们的结果表明，PrP 的柔性 N 端结构域作为一种毒性效应物，受与球状 C 端结构域的分子内相互作用调节。总之，这两个研究领域为朊病毒神经毒性的潜在细胞和分子机制提供了重要线索。然而，在朊病毒科学的这个下一个前沿领域，还有很多工作要做。
