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Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease
Alejandro M. Sevillano, … , K. Peter R. Nilsson, Christina J. Sigurdson
Alejandro M. Sevillano, … , K. Peter R. Nilsson, Christina J. Sigurdson
Published January 27, 2020
Citation Information: J Clin Invest. 2020;130(3):1350-1362. https://doi.org/10.1172/JCI131564.
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Research Article Infectious disease Neuroscience

Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease

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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.

Authors

Alejandro M. Sevillano, Patricia Aguilar-Calvo, Timothy D. Kurt, Jessica A. Lawrence, Katrin Soldau, Thu H. Nam, Taylor Schumann, Donald P. Pizzo, Sofie Nyström, Biswa Choudhury, Hermann Altmeppen, Jeffrey D. Esko, Markus Glatzel, K. Peter R. Nilsson, Christina J. Sigurdson

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Figure 1

PrP180Q/196Q traffics similarly to WT PrPC in primary neurons and in mice.

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PrP180Q/196Q traffics similarly to WT PrPC in primary neurons and in mic...
(A) Representative Western blot of PNGase-F–treated brain extracts from age-matched Prnp180Q/196Q and WT mice reveal similar PrPC expression levels (quantified in right panel) (100–250 day old mice); n = 4/group. (B) PrP immunocytochemistry shows that unglycosylated PrP180Q/196Q traffics to neuronal processes in primary cortical neurons, as does PrP in WT neurons; n = 3 experiments. Scale bars: 10 μm. (C) Representative Western blots of phospholipase C–cleaved (PIPLC-cleaved) PrP180Q/196Q and WT PrP from the surface of cortical neurons show that surface PrPC levels are similar (media); n = 3 experiments. The additional band in the media (~23 kDa) may be a cleaved form of PrP. (D) PrP180Q/196Q and WT PrPC, together with flotillin, localize to detergent-resistant membranes in the brain; n = 3/group. Unpaired, 2-tailed Student’s t test, no significant differences (A and C).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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