title: Sialylation Controls Prion Fatein Vivo.
abstract: Prions or PrPScare proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrPCThe current work tests a new hypothesis that sialylation determines the fate of prions in an organism. To begin, we produced control PrPScfrom PrPCusing protein misfolding cyclic amplification with beads (PMCAb), and also generated PrPScwith reduced sialylation levels using the same method but with partially desialylated PrPCas a substrate (dsPMCAb). Syrian hamsters were inoculated intraperitoneally with brain-derived PrPScor PrPScproduced in PMCAb or dsPMCAb and then monitored for disease. Animals inoculated with brain- or PMCAb-derived PrPScdeveloped prion disease, whereas administration of dsPMCAb-derived PrPScwith reduced sialylation did not cause prion disease. Animals inoculated with dsPMCAb-derived material were not subclinical carriers of scrapie, as no PrPScwas 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 PrPScto secondary lymphoid organs was monitored in wild type mice. PrPScsialylation was found to be critical for effective trafficking of PrPScto secondary lymphoid organs. By 6 hours after inoculation, brain- and PMCAb-derived PrPScwere found in spleen and lymph nodes, whereas dsPMCAb-derived PrPScwas 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 PrPScFurthermore, this work suggests that the sialylation status of PrPScplays an important role in prion lymphotropism.
authors.affiliation: From the Center for Biomedical Engineering and Technology and.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201 and.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: From the Center for Biomedical Engineering and Technology and.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201 and.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Katorcha
authors.affiliation: the Centre for Biological Threats and Special Pathogens, Robert Koch-Institute, 13353 Berlin, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Daus
authors.affiliation: the Centre for Biological Threats and Special Pathogens, Robert Koch-Institute, 13353 Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lasch
authors.affiliation: the Centre for Biological Threats and Special Pathogens, Robert Koch-Institute, 13353 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Beekes
authors.affiliation: From the Center for Biomedical Engineering and Technology and Baskakov@umaryland.edu.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201 and.
authors.forename: Ilia V
authors.identifier: 0000-0003-2821-0942
authors.initials: IV
authors.lastname: Baskakov
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006224:Cricetinae; D008647:Mesocricetus; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D013055:Spectrophotometry, Infrared
chemical_list: D018620:PrPSc Proteins; D011328:Prions; D019158:N-Acetylneuraminic Acid
keywords: Fourier transform IR (FTIR); N-linked glycans; N-linked glycosylation; cyclic amplification; prion; prion disease; protein misfolding; secondary lymphoid organs; sialic acid; sialylation; spleen