Biology of Prion Protein and the TSE Diseases

Pron病或传染性海绵状脑病是人和动物的传染性神经退行性疾病。Prion病的一个主要特征是将正常的宿主蛋白Prion蛋白(PrP)折叠和聚集成疾病相关的蛋白酶抵抗形式(PrPres)，这可能会导致脑损伤。 在2013财年，我们研究了瘙痒病感染小鼠中淀粉样蛋白和非淀粉样蛋白(PrPres)的形成。在表达无锚定PrP的转基因小鼠中，瘙痒病感染后，淀粉样蛋白主要沉积在大脑的血管周围，类似于阿尔茨海默病和一些遗传性脑疾病中出现的脑淀粉样血管病(CAA)。在我们的实验中，PrPres淀粉样蛋白与显微注射的FITC-卵清蛋白(脑间质液(ISF)引流系统的标记物)共同定位，表明ISF血流对PrPres前体的分布可能是导致CAA的发病机制的一部分。这些研究还表明PrPres与毛细血管、动脉和静脉三种类型的血管有关。与转基因小鼠的结果相反，表达锚定PrP的小鼠感染后产生了非淀粉样蛋白PrPres，与血管或ISF示踪剂无关。 在2013财年，我们还研究了PrP表达对红藻氨酸诱导的小鼠癫痫敏感性的影响。其他研究小组之前的研究表明，PrP基因敲除小鼠对这种癫痫发作更敏感。然而，我们使用三种不同的小鼠遗传背景研究PrP缺失的实验表明，PrP缺失有时会使小鼠对红藻氨酸诱导的癫痫发作不那么敏感。此外，利用体内的遗传互补研究，我们发现PrP基因缺失区域的非PrP基因似乎负责与PrP缺失相关的效应。

Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. In FY13 we studied the formation of the amyloid and non-amyloid forms of disease-associated protease-resistant prion protein (PrPres) in scrapie-infected mice. After scrapie infection in transgenic mice expressing anchorless PrP, amyloid is deposited in brain mainly in the perivascular pattern similar to cerebral amyloid angiopathy (CAA) seen in Alzheimers disease and some genetic brain diseases in humans. In our experiments, PrPres amyloid co-localized with microinjected FITC-ovalbumin, a marker of the brain interstitial fluid (ISF) drainage system, suggesting that distribution of precursors of amyloid PrPres by ISF flow might be a part of the pathogenesis leading to CAA. These studies also demonstrated that PrPres was associated with three types of vessels including capillaries, arteries and veins. In contrast to the results seen in transgenic mice, infection of mice expressing anchored PrP gave rise to non-amyloid PrPres which was not associated with blood vessels or with ISF tracers. In FY13 we also studied the effect of PrP expression on sensitivity to kainate-induced seizures in mice. Previous studies by other groups suggested that PrP knockout mice were more sensitive to such seizures. However, our experiments using studying PrP deletion using three different mouse genetic backgrounds showed that PrP deletion sometimes made mice less sensitive to kainate-induced seizures. Furthermore, using genetic complementation studies in vivo, we found that non-PrP genes in the region flanking the deleted PrP gene appeared to be responsible for the effects which appeared to correlate with PrP deletion.