title: Separate mechanisms act concurrently to shed and release the prion protein from the cell.
abstract: The cellular prion protein (PrP (C) ) is attached to the cell membrane via its glycosylphosphatidylinositol (GPI)-anchor and is constitutively shed into the extracellular space. Here, three different mechanisms are presented that concurrently shed PrP (C)  from the cell. The fast α-cleavage released a N-terminal fragment (N1) into the medium and the extreme C-terminal cleavage shed soluble full-length (FL-S) PrP and C-terminally cleaved (C1-S) fragments outside the cell. Also, a slow exosomal release of full-length (FL) and C1-fragment (C1) was demonstrated. The three separate mechanisms acting simultaneously, but with different kinetics, have to be taken into consideration when elucidating functional roles of PrP (C)  and also when processing of PrP (C)  is considered as a target for intervention in prion diseases. Further, in this study it was shown that metalloprotease inhibitors affected the extreme C-terminal cleavage and shedding of PrP (C) . The metalloprotease inhibitors did not influence the α-cleavage or the exosomal release. Taken together, these results are important for understanding the different mechanisms acting in parallel in the shedding and cleavage of PrP (C) .
authors.affiliation: Division of Immunology, Department of Biomedical Sciences and Veterinary Public Health, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Wik
authors.forename: Mikael
authors.initials: M
authors.lastname: Klingeborn
authors.forename: Hanna
authors.initials: H
authors.lastname: Willander
authors.forename: Tommy
authors.initials: T
authors.lastname: Linne
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D055354:Exosomes / Q000378:metabolism; D007700:Kinetics; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018621:PrPC Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000378:metabolism*
chemical_list: D018621:PrPC Proteins; D011328:Prions; D045726:Metalloproteases