GPI-anchor signal sequence influences PrP(C) sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice

The cellular prion protein (PrP(C)) is a cell surface glycoprotein attached to the membrane by a glycosylphosphatidylinositol (GPI)-anchor and plays a critical role in transmissible, neurodegenerative and fatal prion diseases. Alterations in membrane attachment influence PrP(C)-associated signaling, and the development of prion disease, yet our knowledge of the role of the GPI-anchor in localization, processing, and function of PrP(C) in vivo is limited We exchanged the PrP(C) GPI-anchor signal sequence of for that of Thy-1 (PrP(C)GPIThy-1) in cells and mice. We show that this modifies the GPI-anchor composition, which then lacks sialic acid, and that PrP(C)GPIThy-1 is preferentially localized in axons and is less prone to proteolytic shedding when compared to PrP(C). Interestingly, after prion infection, mice expressing PrP(C)GPIThy-1 show a significant delay to terminal disease, a decrease of microglia/astrocyte activation, and altered MAPK signaling when compared to wild-type mice. Our results are the first to demonstrate in vivo, that the GPI-anchor signal sequence plays a fundamental role in the GPI-anchor composition, dictating the subcellular localization of a given protein and, in the case of PrP(C), influencing the development of prion disease.