Biology of Prion Protein and the TSE Diseases

Pron蛋白的表达是对瘙痒病感染的易感性所必需的，但这种作用所需的细胞类型尚不清楚。为了研究体内Pron蛋白表达对细胞类型的特异性影响，研究了在特定细胞类型中表达Pron蛋白的小鼠，如仅限神经元或仅限星形胶质细胞。眼内感染导致仅在神经元或星形胶质细胞表达PrP的小鼠发生瘙痒病，但没有观察到视网膜损伤。相反，在多种细胞类型中表达PrP的小鼠眼内感染会导致严重的视网膜变性。因此，除了神经元和星形胶质细胞外，PrP在其他类型的细胞中的表达是瘙痒病诱导的视网膜损伤所必需的。 使用精确的体内测试，缺乏PrP表达的小鼠被发现在海马区记忆和海马电生理学方面存在缺陷。这些缺陷可以通过转基因的存在而被逆转，转基因只诱导神经元中PrP的表达，这表明在这些测试中，神经元上PrP的存在是正常功能所必需的。 在正常情况下，Prion蛋白被表达为一种由GPI连接物分子锚定在细胞膜上的细胞表面蛋白。为了研究PrP膜锚定在瘙痒病感染中的作用，建立了只表达无锚定PrP的转基因小鼠。在这些转基因小鼠感染后，发现瘙痒病病原体复制并以淀粉样斑的形式在脑内沉积了抗瘙痒病相关蛋白酶的普恩蛋白。然而，这些小鼠在感染后存活了500多天，没有表现出典型的瘙痒病迹象。这些结果表明，抗淀粉样蛋白水解酶的PrP本身可能不能引起通常在Pron疾病中看到的快速脑损伤。最有可能的是，膜锚定的PrP也可能需要接收最大的神经毒性信号。

Prion protein expression is required for susceptibility to scrapie infection, but the cell types required for this effect are not known. To study the cell type-specific effects of prion protein expression in vivo mice expressing prion protein in unique cell types, such as neurons only or astrocytes only, were studied. Intraocular infection induced scrapie brain disease in mice expressing PrP in neurons only, or astrocytes only, however, no retinal damage was observed. In contrast, intraocular infection of mice expressing PrP in multiple cell types lead to severe retinal degeneration. Therefore, PrP expression in additional cell types besides neurons and astrocytes is required for scrapie-induced retinal damage. Using accurate in vivo tests, mice devoid of PrP expression were found to have deficits in hippocampal memory as well as hippocampal electrophysiology. These deficits could be reversed by the presence of a transgene which induced PrP expression in neurons only, indicating that presence of PrP on neurons is required for normal function in these tests. Normally prion protein is expressed as a cell surface protein anchored to the cell membrane by a GPI linker molecule. To study the role of PrP membrane anchoring on scrapie infection, transgenic mice which expressed only an anchorless PrP were generated. After infection of these transgenic mice, scrapie agent was found to replicate and scrapie-associated protease-resistant prion protein was deposited in brain as amyloid plaques. However, these mice survived over 500 days post-infection and failed to show typical signs of scrapie. These results indicate that by itself amyloid protease-resistant PrP may not be able to cause the rapid brain damage usually seen in prion diseases. Most likely membrane-anchored PrP may also be required to receive the maximal neurotoxic signals.