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)折叠和聚集成与疾病相关的形式，这可能会导致脑损伤。在未感染的个体中，正常的PrP通过一种被称为GPI的糖-磷酸-脂连接物分子锚定在外细胞膜上。 在2011财年，我们研究了PrP锚定在细胞膜上的作用，在感染从脑外接种部位转移到脑的过程中。我们发现，细胞膜锚定的PrP对于通过神经(如坐骨神经或舌、眼神经)将感染转移到脑内非常重要。此外，直接静脉接种后通过血液传输到脑内的情况也很少见，而且非常缓慢，需要400至600天。总而言之，这些数据表明，从外周部位将PrP感染性传播到大脑需要表达膜锚定PrP的神经。膜锚定PrP在PrP感染性神经运输中的作用机制尚不清楚。 在2011财年的其他实验中，我们发现正常细胞Pron蛋白的表达能够影响体外培养的小鼠星形胶质细胞对谷氨酸的摄取。PRP基因敲除(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，PrPKO小鼠星形胶质细胞和神经元的混合培养比正常小鼠的类似培养对谷氨酸诱导的兴奋毒性更敏感。这种作用的分子机制目前正在研究中。 在2011财年，利用表达鹿PrP的转基因(TG)小鼠对慢性消耗病(CWD)的感染性进行的实验表明，携带96SS鹿PrP等位基因的转基因小鼠对96SS鹿的CWD或其他PrP等位基因的鹿的CWD具有抗性。因此，到目前为止，这些转基因小鼠似乎对所有形式的CWD感染都有很强的抵抗力。

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.