Biology of Prion Protein and the TSE Diseases

在FY09中，截断朊蛋白（PrP）表达的神经退行性作用被仅在神经元上或仅在星形胶质细胞上表达的正常全长PrP所阻断，表明这种拯救作用不需要特定的细胞类型。与此结论一致的是，细胞分泌的无锚定PrP也可以介导部分但显著的救援作用。此外，仓鼠PrP与小鼠PrP一样有效地介导了这种拯救，因此仓鼠和小鼠之间的物种特异性PrP序列差异对朊病毒疾病物种屏障非常重要，但在截断PrP介导的神经退行性疾病的拯救中并不重要。这一结果表明，这些物种特异性序列差异可能会影响朊病毒疾病中PrP的错误折叠，而它们可能不会影响正常折叠的PrP与参与截断的PrP神经退行性过程的其他脑分子之间的分子相互作用。

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.