Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease
| Autor: | Hermann C. Altmeppen, Christina J. Sigurdson, Timothy D. Kurt, Donald P. Pizzo, Sofie Nyström, Thu H Nam, Katrin Soldau, Jeffrey D. Esko, K. Peter R. Nilsson, Taylor Schumann, Jessica Lawrence, Markus Glatzel, Patricia Aguilar-Calvo, Biswa Choudhury, Alejandro M. Sevillano |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
animal diseases Glycobiology Oligosaccharides Neurodegenerative Medical and Health Sciences Transgenic Prion Diseases Mice chemistry.chemical_compound 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Dominance (genetics) Infectious disease biology Neurodegeneration Brain General Medicine Heparan sulfate Phenotype Cell biology Infectious Diseases 030220 oncology & carcinogenesis Neurological Research Article Glycan Prions Immunology Mutation Missense Mice Transgenic Protein Aggregation Pathological Prion Proteins 03 medical and health sciences Rare Diseases Pathological Polysaccharides medicine Extracellular Animals Protein Processing Post-Translational Transmissible Spongiform Encephalopathy (TSE) medicine.disease Protein Aggregation Brain Disorders nervous system diseases Emerging Infectious Diseases 030104 developmental biology Amino Acid Substitution chemistry Mutation Commentary biology.protein Missense Protein Processing Post-Translational Neuroscience Spongiosis |
| Zdroj: | J Clin Invest The Journal of clinical investigation, vol 130, iss 3 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp(180Q/196Q)), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease. Prnp(180Q/196Q) mice challenged with 2 subfibrillar, non–plaque-forming prion strains instead developed plaques highly enriched in ADAM10-cleaved PrP and heparan sulfate (HS). Intriguingly, a third strain composed of intact, glycophosphatidylinositol-anchored (GPI-anchored) PrP was relatively unchanged, forming diffuse, HS-deficient deposits in both the Prnp(180Q/196Q) and WT mice, underscoring the pivotal role of the GPI-anchor in driving the aggregate conformation and disease phenotype. Finally, knockin mice expressing triglycosylated PrP (Prnp(187N)) challenged with a plaque-forming prion strain showed a phenotype reversal, with a striking disease acceleration and switch from plaques to predominantly diffuse, subfibrillar deposits. Our findings suggest that the dominance of subfibrillar aggregates in prion disease is due to the replication of GPI-anchored prions, with fibrillar plaques forming from poorly glycosylated, GPI-anchorless prions that interact with extracellular HS. These studies provide insight into how PTMs impact PrP interactions with polyanionic cofactors, and highlight PTMs as a major force driving the prion disease phenotype. |
| Databáze: | OpenAIRE |
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