Biology of Prion Protein and the TSE Diseases

朊病毒病或传染性海绵状脑病是人类和动物的传染性神经退行性疾病。朊病毒疾病的一个主要特征是正常宿主蛋白朊病毒蛋白（PrP）的重折叠和聚集成可能导致脑损伤的疾病相关形式。在未感染的个体中，正常的PrP通过糖-磷酸-脂质连接分子（称为GPI）锚定在细胞外膜上。 在2011财年，我们研究了PrP锚定在细胞膜上在将感染从脑外接种部位转运至脑的过程中的作用。我们发现，细胞膜锚定的PrP是非常重要的运输感染通过神经，如坐骨神经或神经从舌头或眼睛。此外，直接静脉接种后通过血液转运到大脑的情况也很少见，而且非常缓慢，需要400至600天。总之，这些数据表明，朊病毒感染性从外周部位传播到大脑需要表达膜锚定PrP的神经。膜锚定PrP在朊病毒感染性神经转运中的作用机制仍不清楚。 在2011财年的其他实验中，我们发现正常细胞朊病毒蛋白的表达能够影响体外小鼠星形胶质细胞对谷氨酸的吸收。PrP敲除（KO）星形胶质细胞转运谷氨酸的速度几乎是正常星形胶质细胞的两倍。此外，混合培养的星形胶质细胞加上神经元从PrPKO小鼠谷氨酸诱导的兴奋性毒性比类似的文化从正常小鼠更敏感。这种效应的分子机制目前正在研究中。 在FY 11中，在表达鹿PrP的转基因（tg）小鼠中使用慢性消耗性疾病（CWD）感染性的实验表明，具有96 SS鹿PrP等位基因的tg小鼠对来自96 SS鹿或来自具有其他PrP等位基因的鹿的CWD具有抗性。因此，这些tg小鼠似乎对迄今为止测试的所有形式的CWD的感染具有非常强的抵抗力。

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 form which may contribute to brain damage. In uninfected individuals normal PrP is anchored to the outer cell membrane by a sugar-phosphate-lipid linker molecule, known as GPI. In FY11 we investigated the role of anchoring of PrP to the cell membrane in the process of transport of infection to the brain from sites of inoculation outside the brain. We found that cell membrane anchored PrP was very important for the transport of infection to brain via nerves such as the sciatic nerve or nerves from the tongue or eye. Furthermore, transport to brain by blood after direct intravenous inoculation was also rare and very slow, requiring 400 to 600 days. Together these data indicate that spread of prion infectivity to brain from peripheral sites requires nerves which express membrane anchored PrP. The mechanism of the role of membrane anchored PrP in nerval transport of prion infectivity remains unknown. In other experiments in FY11, we found that expression of normal cellular prion protein was able to influence glutamate uptake by mouse astrocytes in vitro. PrP knockout (KO) astrocytes transported glutamate almost twice as fast as normal astrocytes. Furthermore, mixed cultures of astrocytes plus neurons from PrPKO mice were more sensitive to glutamate-induced excitotoxicity than similar cultures from normal mice. The molecular mechanism of this effect is currently under investigation. In FY11 experiments using chronic wasting disease (CWD) infectivity in transgenic (tg) mice expressing deer PrP showed that tg mice with the 96SS deer PrP allele were resistant to CWD from 96SS deer or from deer with other PrP alleles. Thus these tg mice appeared to have a very strong resistance to infection by all forms of CWD tested to date.