Biology of Prion Protein and the TSE Diseases

Pron蛋白的表达是Pron感染和疾病所必需的，但不同细胞类型在不同感染器官中的作用尚不清楚。为了解决这个问题，我们使用了只在神经元或多种细胞类型中表达PrP的转基因小鼠。在多种细胞类型表达PrP的小鼠眼内接种瘙痒病后，我们观察到视网膜细胞变性和视网膜小胶质细胞激活。在仅在神经元中表达PrP的小鼠中，检测到异常PrPres的原因是没有视网膜退化或小胶质细胞激活。这种差异在脑组织中看不到，因为两个品系的小鼠脑组织的激活和退化都很广泛。这些结果提示，羊痒病感染后视网膜和脑内小胶质细胞的激活机制不同，视网膜小胶质细胞PrP的表达可能是这一过程中的一个重要因素。 获得了表达两种不同等位基因的鹿普恩蛋白转基因小鼠。携带G96等位基因的小鼠对4种不同来源的野生型CWD病原体引起的疾病易感。相比之下，S96小鼠对所有这些池都有抵抗力。由于带有S96等位基因的鹿对CWD具有部分抗性，因此可能只有一小部分CWD品系可以感染这种鹿。另外，S96鹿可能对所有CWD菌株都有其他的抗性机制。我们目前正试图通过给我们的小鼠接种从受感染的S96鹿中提取的CWD试剂来区分这些可能性。

Prion protein expression is required for prion infection and disease, but the roles of individual cell types in different infected organs is not yet clear. To approach this problem we have used transgenic mice expressing PrP in neurons only or in multiple cell types. After intraocular scrapie inoculation in mice expressing PrP in multiple cell types we noted degeneration of retinal cells and retinal microglial activation. In mice expressing PrP in neurons only, abnormal PrPres was detected by there was no retinal degeneration or microglial activation. This difference was not seen in brain tissue where activation and degeneration were extensive in both mouse strains. These results suggest that different microglial activation mechanisms occur after scrapie infection in retina and brain, and that PrP expression by retinal microglia might be an important factor in this process. Transgenic mice expressing two different alleles of deer prion protein were generated. Mice with the G96 allele were found to be susceptible to disease induced by 4 different pools of wild type CWD agent from deer or elk. In contrast S96 mice were resistant to all these pools. Since deer with the S96 allele are partially resistant to CWD it is possible that only a small number of CWD strain can infect such deer. Alternatively S96 deer might have other mechanisms of resistance to all strains of CWD. We are currently trying to distinguish between these possibilities by inoculating our mice with CWD agent derived from infected S96 deer.