TSE Prion Cell Biology

tse是一组影响多种哺乳动物的神经退行性疾病，包括绵羊和山羊（痒病），宫颈（慢性消耗性疾病）和人类（克雅氏病）。我们的研究重点是朊蛋白（PrP），因为该蛋白在控制TSE发病机制的许多方面发挥着关键作用，如疾病易感性和种间传播。TSE疾病的中心事件涉及正常宿主细胞朊病毒蛋白（PrPC或PrP-sen）转化为部分蛋白酶抗性，聚集性，疾病相关亚型（PrPSc或PrP-res）。tse诱导的病理通常与PrP-res沉积有关，但神经退行性变的机制尚不清楚。被称为朊病毒的传染因子的性质仍不确定，但被认为主要由错误折叠的PrP组成，可能与另一个宿主附属分子复合。PrP-sen是一种糖基磷脂酰肌醇（GPI）锚定的糖蛋白，大多数在体内产生的PrP-res含有这种GPI锚定蛋白。正常和疾病相关的PrP异构体的膜结合可能影响朊病毒疾病的许多特征和PrP-sen功能。我们的工作重点是阐明朊病毒的摄取、复制和传播机制，以及确定哺乳动物朊病毒的生化组成和研究导致这些朊病毒感染表型的因素，这是所有蛋白质错误折叠疾病的一个独特特征。

TSEs are a group of neurodegenerative diseases affecting a wide variety of mammals including sheep and goats (scrapie), cervid spp. (chronic wasting disease), and humans (Creutzfeldt-Jakob disease). Our studies are focused on the prion protein (PrP) due to the critical role of this protein in controlling many aspects of TSE pathogenesis such as susceptibility to disease and interspecies transmission. A central event in TSE disease involves the conversion of the normal host cellular prion protein (PrPC or PrP-sen) to a partially protease-resistant, aggregated, disease-associated isoform (PrPSc or PrP-res). TSE-induced pathology is usually associated with PrP-res deposition, but the mechanism of neurodegeneration is not understood. The nature of the infectious agent, called a prion, remains uncertain but is thought to be composed primarily of misfolded PrP, perhaps in complex with another host accessory molecule(s). PrP-sen is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, and the majority of PrP-res produced in vivo contains this GPI anchor. Membrane association of both normal and disease-associated PrP isoforms may influence many features of prion disease and PrP-sen function. Our work is focused on elucidating mechanisms of uptake, replication, and spread of prions, in addition to determining the biochemical composition of mammalian prions and investigating factors that contribute to imparting the infectious phenotype to these prions, a unique feature among all protein misfolding diseases. Over the past year we have: 1) continued our characterization of how PrP-res is internalized and trafficked in neuronal cells by confocal microscopy, expanding our studies to primary neuronal culture systems; 2) validated and optimized new methods to specifically tag PrP-sen molecules to visualize their trafficking in uninfected cells and during the course of scrapie infection; 3) created new compounds for protein labeling that allow analysis by a variety of detection methods; and 4) further characterized our novel cell culture models to visualize the trafficking of other modified prion and amyloid proteins by confocal microscopy.