Sialylation Controls Prion Fate .

Prions or PrP are proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrP The current work tests a new hypothesis that sialylation determines the fate of prions in an organism. To begin, we produced control PrP from PrP using protein misfolding cyclic amplification with beads (PMCAb), and also generated PrP with reduced sialylation levels using the same method but with partially desialylated PrP as a substrate (dsPMCAb). Syrian hamsters were inoculated intraperitoneally with brain-derived PrP or PrP produced in PMCAb or dsPMCAb and then monitored for disease. Animals inoculated with brain- or PMCAb-derived PrP developed prion disease, whereas administration of dsPMCAb-derived PrP with reduced sialylation did not cause prion disease. Animals inoculated with dsPMCAb-derived material were not subclinical carriers of scrapie, as no PrP was detected in brains or spleen of these animals by either Western blotting or after amplification by serial PMCAb. In subsequent experiments, trafficking of brain-, PMCAb-, and dsPMCAb-derived PrP to secondary lymphoid organs was monitored in wild type mice. PrP sialylation was found to be critical for effective trafficking of PrP to secondary lymphoid organs. By 6 hours after inoculation, brain- and PMCAb-derived PrP were found in spleen and lymph nodes, whereas dsPMCAb-derived PrP was found predominantly in liver. This study demonstrates that the outcome of prion transmission to a wild type host is determined by the sialylation status of the inoculated PrP Furthermore, this work suggests that the sialylation status of PrP plays an important role in prion lymphotropism.