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。朊病毒病的主要特征是正常宿主蛋白质朊病毒蛋白（PrP）的重折叠和聚集，成为可能导致脑损伤的疾病相关蛋白酶抗性形式（PrPres）。在2019年度，我们通过跟踪朊病毒感染后视网膜感光细胞损伤的进展，在体内扩展了小胶质细胞在宿主防御朊病毒病中的作用的研究。 在视网膜中，朊病毒感染导致感光细胞的破坏，伴随着小胶质细胞大量浸润到感光细胞区域。在与眼功能相关的蛋白质的各种突变相关的人类色素性视网膜炎中观察到类似的病理模式，并且在具有这些相同突变的小鼠模型中观察到类似的结果。因此，小胶质细胞被怀疑是视网膜色素变性的致病过程中的重要介质，这也可能是真的朊病毒诱导的视网膜疾病。 在2019财年，我们使用CSF-1 R的强效抑制剂PLX 5622口服治疗，在朊病毒感染后不久和感染过程中消除了小鼠中枢神经系统和视网膜中78%至90%的小胶质细胞。然后，我们在感染后不同时间对具有正常或消融的小胶质细胞的小鼠进行视网膜病理学观察。结果表明，朊病毒视网膜疾病不需要小胶质细胞作为发病机制的介质的存在。事实上，在没有小胶质细胞的情况下，感光细胞的破坏稍快。因此，朊病毒感染似乎通过在感光细胞层的内节上形成聚集的异常朊病毒蛋白质的沉积物而直接损害感光细胞。 未来的实验将旨在更精确地确定细胞类型的目标和异常朊病毒蛋白的细胞位置，使用超微结构检查和免疫金检测方法。

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.