Biology of Prion Protein and the TSE Diseases

传染性海绵状脑病（TSE）或朊病毒疾病，需要正常宿主朊病毒蛋白（PrP）的表达，用于感染因子的复制和疾病发病机制的表现。我们已经研究了不同的脑细胞类型，包括神经元和星形胶质细胞中的PrP表达的影响，通过使用转基因小鼠，表达PrP的神经元，星形胶质细胞，或在多种细胞类型。所有这三种类型的老鼠都容易感染羊瘙痒病，并且都死于这种疾病。令人惊讶的是，当PrP仅在星形胶质细胞上表达时的病理学与当PrP在神经元以及多种其他细胞类型中表达时观察到的病理学相似。进一步检查发现异常PrP定位于星形胶质细胞周围，但这些星形胶质细胞未受损。相反，损伤局限于邻近的神经元。电镜下可见异常的PrP分布于星形胶质细胞及其周围的神经突周围。因此，神经致病性的致病过程似乎间接介导的神经元异常PrP从星形胶质细胞。 在单独的实验中，从正常到异常的PrP的转换过程中进行了研究，在体外无细胞系统中使用N-末端PrP缺失突变体，以检查N-末端在这个生化过程中的作用。从32-98的残基的缺失引起PrP转化的显著降低，以及改变转化的蛋白质的结构，使其在从130至155的残基处更容易被蛋白酶K消化。当使用来自羊瘙痒病感染的仓鼠的PrP转换非缺失小鼠PrP时，观察到类似的变化。这些结果表明，改变结构的异常PrP可能是一个因素，在适应物种之间的转换过程中跨物种感染。

Transmissible spongiform encephalopathies (TSE), or prion diseases, require the expression of normal host prion protein (PrP) for both replication of the infectious agent and for the manifestation of the disease pathogenesis. We have studied the effect of PrP expression in different brain cell types including neuron and astrocytes by using transgenic mice which express PrP in neurons only, astrocytes only, or in multiple cell types. All three types of mice are susceptible to scrapie infection and all succumb to the disease. Surprisingly the pathology when PrP was expressed only on astrocytes was similar to that seen when PrP was expressing in neurons as well as in multiple other cell types. Further examination revealed that abnormal PrP was localized around astrocytes, but these astrocytes were not damaged. In contrast the damage was localized to adjacent neurons. By electron microscopy the abnormal PrP was found on the astrocytes and also around neurotic process in the near vicinity of such astrocytes. Thus the neuropathogenic pathogenic process appeared to be mediated in neurons indirectly by abnormal PrP from astrocytes. In separate experiment the process of conversion of from normal to abnormal PrP was studied in vitro in a cell-free system using N-terminal PrP deletion mutants in order to examine the role of the N-terminus in this biochemical process. Deletion of residues from 32-98 caused a marked reduced in PrP conversion as well as altering the structure of the converted protein to make it more susceptible to protease K digestion at residues from 130 to 155. A similar change was observed when non-deleted mouse PrP was converted using PrP from scrapie-infected hamsters. These results suggested that altered structure of abnormal PrP might be a factor in the adaptation of the conversion process between species following cross-species infection.