Biology of Prion Protein and the TSE Diseases

在FY 09中，截短型朊病毒蛋白（PrP）表达的神经退行性作用被仅在神经元或仅在星形胶质细胞上表达的正常全长PrP阻断，表明这种拯救作用不需要特定的细胞类型。与此结论一致，无锚PrP分泌的细胞也可以介导部分，但显着的救援效果。此外，仓鼠PrP在介导这种拯救中与小鼠PrP一样有效，因此仓鼠和小鼠之间的物种特异性PrP序列差异对于朊病毒疾病物种屏障非常重要，但在由截短PrP介导的神经变性的拯救中并不重要。这一结果意味着，这些物种特异性序列差异可能会影响朊病毒疾病中的PrP错误折叠，而它们可能不会影响正常折叠的PrP和其他参与截短PrP神经退行性过程的脑分子之间的分子相互作用。 在C57 BL/10野生型小鼠以及表达无锚PrP的转基因小鼠中研究羊瘙痒病感染的工作显示，棕色和白色脂肪组织中的感染性滴度较高。进一步的实验证明，患有慢性消耗病的鹿的脂肪组织也具有明显的脂肪朊病毒感染性。因此，在评估朊病毒病在动物物种间传播的风险时，应考虑脂肪组织。 在其他实验中，研究了细胞因子和趋化因子在羊瘙痒病发病机制和宿主对羊瘙痒病诱导的疾病的反应中的可能作用。24种细胞因子和趋化因子的蛋白质水平进行了分析，通过多重分析，在脑匀浆的羊瘙痒症感染和未感染的C57 BL/10小鼠，PrPnull小鼠和转基因小鼠只表达无锚PrP。在感染的大脑中检测到10种细胞因子或趋化因子水平的升高。细胞因子也研究了刺激痒病感染或未感染的脑匀浆的小胶质细胞和星形胶质细胞的培养液。结果表明，在瘙痒症脑刺激后，小胶质细胞仅产生两种细胞因子，而星形胶质细胞产生十种。这些对羊瘙痒病感染或体外刺激的反应更可能是对羊瘙痒病诱导的损伤的反应，而不是羊瘙痒病致病性疾病诱导过程的重要部分。

In FY09 the neurodegenerative effect of expression of truncated prion protein (PrP) was blocked by expression of normal full-length PrP on neurons only or astrocytes only, indicating that there was not a specific cell type required for this rescue effect. In agreement with this conclusion, anchorless PrP secreted from cells could also mediate a partial but significant rescue effect. Furthermore, hamster PrP was as efficient as mouse PrP in mediating this rescue, so the species-specific PrP sequence differences between hamster and mouse, which are so important for prion disease species-barriers, are not important in the rescue from neurodegeneration mediated by truncated PrP. This result implies that these species-specific sequence differences might influence PrP misfolding in prion diseases, whereas they might not influence molecular interactions between normally folded PrP and other brain molecules involved in the truncated PrP neurodegenerative process. Work studying scrapie infection in C57BL/10 wild-type mice as well as in transgenic mice expressing anchorless PrP has shown high infectivity titers in brown and white fat tissues. Further experiments have demonstrated that fat tissues of deer with chronic wasting disease also have significant prion infectivity in fat. Therefore fat tissue should be considered in assessment of risk of prion disease spread among animal species. In other experiments the possible roles of cytokines and chemokines in the scrapie pathogenesis and the host response to scrapie-induced disease was studied. Protein levels of 24 cytokines and chemokines were analyzed by multiplex analysis in brain homogenates of scrapie-infected and uninfected C57BL/10 mice, PrPnull mice and transgenic mice expressing only anchorless PrP. Elevation of levels of 10 cytokines or chemokines were detected in infected brains. Cytokines were also studied in culture fluids of microglia and astroglia stimulated by scrapie-infected or uninfected brain homogenates. The results indicated that after stimulation by scrapie brain, microglia made only two cytokines, whereas astroglia made ten. These responses to scrapie infection or in vitro stimulation were more likely responses to the damage induced by scrapie rather than an essential parts of the scrapie pathogenic disease-inducing process.