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正常宿主蛋白Prion蛋白(PrP)被折叠和聚集成疾病相关的蛋白酶抵抗形式(PrPres)，这可能导致脑损伤。在19财年，我们通过脑内途径跟踪PrP感染后视网膜光感受器损伤的进展，扩大了我们对小胶质细胞在体内宿主防御Prion病中的作用的研究。 在视网膜中，Pron感染导致光感受器细胞的破坏，并伴随着大量的小胶质细胞向光感受器细胞区域的渗透。在与眼功能相关的蛋白质的各种突变导致的人类视网膜色素变性中也发现了类似的病理模式，在具有相同突变的小鼠模型中也看到了类似的结果。因此，小胶质细胞被怀疑是视网膜色素变性发病过程中的重要介质，这一点在Pron诱导的视网膜疾病中也可能是如此。 在19财年，我们使用了一种有效的CSF-1R抑制剂PLX5622的口服治疗，在Pron感染后不久和过程中，消除了小鼠中枢神经系统和视网膜中78%到90%的小胶质细胞。然后，我们观察了感染后不同时间小胶质细胞正常或消融的小鼠的视网膜病理。结果表明，蛋白视网膜疾病不需要小胶质细胞的存在作为发病机制的中介。事实上，在没有小胶质细胞的情况下，光感受器细胞的破坏略快一些。因此，Prion感染似乎通过在光感受器层内段形成聚集的异常Pron蛋白沉积来直接损伤光感受器细胞。 未来的实验将致力于利用超微结构检查和免疫金检测方法，更准确地识别目标细胞类型和异常Pron蛋白的细胞位置。

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 FY19, we extended our studies of the role of microglia in host defense against prion disease in vivo by following the progression of retina photoreceptor damage following prion infection via the intracerebral route. In retina, prion infection causes destruction of photoreceptor cells accompanied by a massive infiltration of microglia into the photoreceptor cell region. A similar pattern of pathology is seen in human retinitis pigmentosa associated with various mutations in proteins related to ocular function, and similar results have been seen in mouse models with these same mutations. Therefore, microglia are suspected to be important mediators of the pathogenic process in retinitis pigmentosa and this may also be true for prion-induced retinal disease. In FY19, we used oral treatment with a potent inhibitor of CSF-1R, PLX5622, to eliminate 78 to 90% of microglia from mouse central nervous system and retina shortly after and during the course of prion infection. Then we followed retinal pathology at various times post infection in mice with normal or ablated microglia. The results showed that prion retinal disease did not require the presence of microglia as mediators of pathogenesis. In fact, the destruction of photoreceptor cells was slightly faster in the absence of microglia. Thus, prion infection appeared to directly damage photoreceptor cells by forming deposits of aggregated abnormal prion protein located on the inner segment of the photoreceptor layer. Future experiments will be aimed at identifying more precisely the cell types targeted and the cellular location of the abnormal prion protein using ultrastructural examination and immunogold detection methods.