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Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease.
- Source :
-
Journal of Clinical Investigation . Mar2020, Vol. 130 Issue 3, p1350-1362. 13p. - Publication Year :
- 2020
-
Abstract
- 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 (Prnp180Q/196Q), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease. Prnp180Q/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 Prnp180Q/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 (Prnp187N) 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PRION diseases
*PRIONS
*GLYCANS
*BOVINE spongiform encephalopathy
*POST-translational modification
*HEPARAN sulfate
*PROTEINS
*RESEARCH
*GENETIC mutation
*ANIMAL experimentation
*RESEARCH methodology
*EVALUATION research
*MEDICAL cooperation
*COMPARATIVE studies
*OLIGOSACCHARIDES
*RESEARCH funding
*AMINO acids
*MICE
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 142176146
- Full Text :
- https://doi.org/10.1172/JCI131564