Propagation of Lipid-Anchored Prion Aggregates

传染性海绵状脑病（Transmissible spongiform encephalopathies，TSE），也称为朊病毒病，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（羊瘙痒病）、鹿属（cervid spp.）（慢性消耗性疾病）和人类（克雅氏病）。 TSE疾病的中心事件涉及正常宿主细胞朊病毒蛋白（PrPC）转化为部分蛋白酶抗性、聚集的疾病相关同种型（PrPSc）。 TSE引起的病理学改变通常与PrP-res沉积有关，但神经退行性变的机制尚不清楚。 与朊病毒疾病一样，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质的积累有关。 朊病毒在宿主之间和宿主内传播的关键过程包括PrPSc的神经侵袭和细胞间扩散。 PrP通过糖基磷脂酰肌醇（GPI）-锚的膜缔合可能在调节这些过程中发挥重要作用。 我们在这个项目中的工作重点是阐明GPI和其他形式的膜锚定在调节聚集和细胞间扩散的聚集倾向的蛋白质的作用。 2012年，我们继续进行实验，研究膜锚定如何允许蛋白质聚集体作为朊病毒繁殖。 到目前为止，我们已经确定了至少一种支持朊病毒传播的膜锚定新形式。

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 membrane association of PrP via a glycosylphosphatidylinositol (GPI)-anchor may have an important role in modulating these processes. Our work in this project is focused on elucidating the role of GPI and other forms of membrane anchoring in modulating the aggregation and intercellular spread of aggregation-prone proteins. In 2012, we have continued experiments to investigate how membrane anchoring can allow the propagation of protein aggregates as prions. We have thus far identified at least one new form of membrane anchoring that supports prion propagation.