Mechanisms of prion spread

描述(申请人提供)：Prion病是由PrPSc蛋白聚集态引起的致命性神经退行性疾病。Prion是唯一作为传染病自然传播的蛋白质聚集体，最近，人与人之间的传播可能是通过输注受Prion污染的血液发生的。大多数自然传播的病例是通过外周暴露，然后病毒传播到中枢神经系统。尽管普恩被认为通过外周神经传播到中枢神经系统，但神经传递的分子机制尚不清楚。出于这个原因，这项授权申请的一个主要目标是了解Pron聚集体是如何传播到中枢神经系统的。我们假设Pron通过逆行轴突运输进行繁殖，并将使用体外和体内实验模型解决这一假设。为了实现这一目标，提出了三个目标。在第一个目标中，我们将使用在轴突终末和细胞体之间有液体分离的分区神经元培养来测试PrPSc轴突运输的机制。我们还将在体内评估Pron菌株的外周神经运输。在第二个目标中，我们将测量高毒力的容易传播到中枢神经系统的病毒株的结构特性。在第三个目标中，我们将利用转基因小鼠和表达PrPC的具有或不具有GPI锚的原代神经元来确定PrPC的GPI膜锚在PrPC扩散到大脑中的作用。我们期望这些研究将提供有关病毒传播基本机制的关键缺失信息，这些信息对于开发免疫疗法和新的治疗策略以防止或阻止疾病进展至关重要。 与公共卫生相关：Prion感染是由错误折叠的蛋白质入侵神经系统并最终导致进行性恶化和死亡引起的。在大多数情况下，Pron感染通过食源性污染传播，并被认为通过神经传播到大脑。我们建议研究Prion如何扩散到大脑的潜在机制，以开发新的策略来阻止Prion的传播。

DESCRIPTION (provided by applicant): Prion diseases are fatal neurodegenerative disorders caused by an aggregated form of the prion protein, PrPSc. Prions are the only protein aggregates that are naturally transmitted as an infectious disease, and most recently, human to human transmission likely occurred by transfusion of prion-contaminated blood. Most cases of natural transmission occur through a peripheral exposure followed by prion spread to the CNS. Although prions are thought to spread via peripheral nerves to the CNS, the molecular mechanisms underlying neuronal transit are unclear. For this reason, a major goal of this grant application is to understand how prion aggregates spread to the CNS. We hypothesize that prions propagate by retrograde axonal transport and will address this hypothesis using in vitro and in vivo experimental models. To accomplish this goal, three aims are proposed. In the first aim, we will test the mechanism of PrPSc axonal transport using compartmentalized neuronal cultures that have a liquid separation between the axon terminals and the cell bodies. We will additionally assess the peripheral nerve transport of prion strains in vivo. In the second aim, we will measure the structural properties of the highly virulent prion strains that readily spread to he CNS. In the third aim, we will determine the role of the GPI membrane anchor of PrPC on prion spread to the brain using transgenic mice and primary neurons that express PrPC possessing or lacking the GPI anchor. We expect that these studies will provide critical missing information on the basic mechanisms of prion spread that will be essential for the development of immunotherapies and novel therapeutic strategies to prevent or arrest disease progression. PUBLIC HEALTH RELEVANCE: Prion infections are caused by misfolded proteins that invade the nervous system and ultimately lead to progressive deterioration and death. In most cases, prion infections are transmitted by foodborne contamination and are thought to spread through nerves into the brain. We propose to investigate the underlying mechanisms for how prions spread to the brain in order to develop new strategies to block prion propagation.