PLoS pathogens, 2019-01, Vol.15 (1), p.e1007520-e1007520
2019
Details
- Autor(en) / Beteiligte
- Titel
- GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice
- Ist Teil von
- PLoS pathogens, 2019-01, Vol.15 (1), p.e1007520-e1007520
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7374, 1553-7366eISSN: 1553-7374DOI: 10.1371/journal.ppat.1007520Titel-ID: cdi_plos_journals_2251134107
- Format
- –
- Schlagworte
- Animals, Axons, Biochemistry, Biology, Biology and Life Sciences, Butenandt, Adolf, Cell surface, Composition, Disease, Disease Models, Animal, Glycoproteins, Glycosylphosphatidylinositol, Glycosylphosphatidylinositols - metabolism, Glycosylphosphatidylinositols - physiology, Kinases, Lipids, Localization, MAP kinase, Medicine and Health Sciences, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia, N-Acetylneuraminic Acid - metabolism, Neuropathology, Pathogenesis, Physical Sciences, Prion Diseases - genetics, Prion Diseases - metabolism, Prion protein, Prion Proteins - metabolism, Prions, Prions - genetics, Prions - metabolism, Protein Sorting Signals - physiology, Protein Transport - physiology, Proteins, Proteolysis, PrPC Proteins - metabolism, PrPC Proteins - physiology, Research and Analysis Methods, Shedding, Signal Transduction, Signaling, Terminal diseases