Prion protein post-translational modifications modulate heparan sulfate binding and limit aggregate size in prion disease

• Published in: Neurobiology of disease Vol. 142; p. 104955
• Main Authors: Callender, Julia A., Sevillano, Alejandro M., Soldau, Katrin, Kurt, Timothy D., Schumann, Taylor, Pizzo, Donald P., Altmeppen, Hermann, Glatzel, Markus, Esko, Jeffrey D., Sigurdson, Christina J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2020; Elsevier
• Subjects: ADAM10 cleavage; Amyloid; Animals; Brain - metabolism; Cell Membrane - metabolism; Female; Glycans; Glycosaminoglycans; Glycosylation; Heparitin Sulfate - metabolism; Male; Mice; Mice, Transgenic; Neurodegeneration; Prion Diseases - genetics; Prion Diseases - metabolism; Prion Proteins - genetics; Prion Proteins - metabolism; Prion strains; Protein Aggregates - genetics; Protein Binding - genetics; Protein misfolding; Protein Processing, Post-Translational - genetics; Glycosaminoglycans; Protein misfolding; Neurodegeneration; Prion strains; ADAM10 cleavage; Amyloid; Glycans; Glycosylation
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2020.104955

Many aggregation-prone proteins linked to neurodegenerative disease are post-translationally modified during their biogenesis. In vivo pathogenesis studies have suggested that the presence of post-translational modifications can shift the aggregate assembly pathway and profoundly alter the disease phenotype. In prion disease, the N-linked glycans and GPI-anchor on the prion protein (PrP) impair fibril assembly. However, the relevance of the two glycans to aggregate structure and disease progression remains unclear. Here we show that prion-infected knockin mice expressing an additional PrP glycan (tri-glycosylated PrP) develop new plaque-like deposits on neuronal cell membranes, along the subarachnoid space, and periventricularly, suggestive of high prion mobility and transit through the interstitial fluid. These plaque-like deposits were largely non-congophilic and composed of full length, uncleaved PrP, indicating retention of the glycophosphatidylinositol (GPI) anchor. Prion aggregates sedimented in low density fractions following ultracentrifugation, consistent with oligomers, and bound low levels of heparan sulfate (HS) similar to other predominantly GPI-anchored prions. Collectively, these results suggest that highly glycosylated PrP primarily converts as a GPI-anchored glycoform, with low involvement of HS co-factors, limiting PrP assembly mainly to oligomers. Since PrPC is highly glycosylated, these findings may explain the high frequency of diffuse, synaptic, and plaque-like deposits in the brain as well as the rapid conversion commonly observed in human and animal prion disease. •Knockin mice expressing tri-glycosylated PrPC develop novel plaque-like deposits upon prion infection.•Tri-glycosylated PrPSc forms mobile oligomers that accumulate perineuronally, periventricularly, and adjacent to meninges.•Tri-glycosylated PrPSc binds low levels of heparan sulfate, unlike unglycosylated PrPSc.•PrP post-translational modifications profoundly alter prion aggregate assembly pathways.