Propagation of Lipid-Anchored Prion Aggregates

传染性海绵状脑病(TSEs)，又称Pron病，是一组影响多种哺乳动物的神经退行性疾病，包括绵羊、山羊(瘙痒病)、鹿瘟(Cervid Spp)。(慢性消耗性疾病)和人类(克雅氏病)。TSE病的一个中心事件涉及将正常宿主细胞内的Prion蛋白(PrPC)转换为部分抗蛋白酶的、聚集的、疾病相关的亚型(PrPSc)。TSE诱导的病理通常与PrP-res沉积有关，但其神经退行性变的机制尚不清楚。与Pron疾病一样，其他神经退行性疾病涉及病理性蛋白质聚集体的沉积，包括阿尔茨海默病和帕金森氏病。总的来说，这些疾病被称为蛋白质错误折叠疾病，因为它们与错误折叠的宿主蛋白的积累有关。PrPSc在宿主之间和宿主内部传递的关键过程包括神经入侵和PrPSc的细胞间传播。PrP的糖基磷脂酰肌醇(GPI)锚定可能在调控这些过程中起着重要作用。我们在这个项目中的工作集中在阐明GPI锚定在调节聚集倾向蛋白的聚集和细胞间扩散中的作用。 2009年，我们进一步研究了新的细胞培养模型，可视化了哺乳动物细胞中GPI锚定的酵母蛋白聚集体的形成、裂解和细胞间扩散；以及2)用免疫电子显微镜表征了这些聚集体的超微结构。这项工作导致了目前正在审查的一份手稿。

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, 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). A central event in TSE disease involves the conversion of the normal host cellular prion protein (PrPC) to a partially protease-resistant, aggregated, disease-associated isoform (PrPSc). TSE-induced pathology is usually associated with PrP-res deposition, but the mechanism of neurodegeneration is not understood. Like prion diseases, other neurodegenerative diseases involve the deposition of pathological protein aggregates including Alzheimers and Parkinsons disease. Collectively, these diseases are termed protein misfolding diseases because they are associated with the accumulation of misfolded host proteins. Critical processes for transmission of prions between and within hosts include neuroinvasion and intercellular spread of PrPSc. The glycosylphosphatidylinositol (GPI)-anchor of PrP may have an important role in modulating these processes. Our work in this project is focused on elucidating the role of GPI anchoring in modulating the aggregation and intercellular spread of aggregation-prone proteins. In 2009, we have: 1) further studied novel cell culture models and visualized the formation, fragmentation, and intercellular spread of aggregates of a GPI-anchored yeast prion protein in mammalian cells; and 2) characterized the ultrastructure of these aggregates by immunoelectron microscopy. This work has led to one manuscript currently under review.