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

Puig, B; Altmeppen, H C; Linsenmeier, L; Chakroun, K; Wegwitz, F; Piontek, U K; Tatzelt, J; Bate, C; Magnus, T; Glatzel, M

Abstract

The cellular prion protein (PrPC) 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 PrPC-associated signaling, and the development of prion disease, yet our knowledge of the role of the GPI-anchor in localization, processing, and function of PrPC in vivo is limited We exchanged the PrPC GPI-anchor signal sequence of for that of Thy-1 (PrPCGPIThy-1) in cells and mice. We show that this modifies the GPI-anchor composition, which then lacks sialic acid, and that PrPCGPIThy-1 is preferentially localized in axons and is less prone to proteolytic shedding when compared to PrPC. Interestingly, after prion infection, mice expressing PrPCGPIThy-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 PrPC, influencing the development of prion disease.

Citation

Puig, B., Altmeppen, H. C., Linsenmeier, L., Chakroun, K., Wegwitz, F., Piontek, U. K., Tatzelt, J., Bate, C., Magnus, T., & Glatzel, M. (2019). GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice. PLoS Pathogens, 15(1), e1007520. https://doi.org/10.1371/journal.ppat.1007520

• Journal Article Type: Article
• Acceptance Date: Dec 11, 2018
• Publication Date: Jan 4, 2019
• Deposit Date: Jan 25, 2019
• Publicly Available Date: Jan 28, 2019
• Journal: PLoS Pathogens
• Print ISSN: 1553-7366
• Electronic ISSN: 1553-7374
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 1
• Pages: e1007520
• DOI: https://doi.org/10.1371/journal.ppat.1007520
• Public URL: https://rvc-repository.worktribe.com/output/1384128