Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease
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Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease. / Sevillano, Alejandro M; Aguilar-Calvo, Patricia; Kurt, Timothy D; Lawrence, Jessica A; Soldau, Katrin; Nam, Thu H; Schumann, Taylor; Pizzo, Donald P; Nyström, Sofie; Choudhury, Biswa; Altmeppen, Hermann; Esko, Jeffrey D; Glatzel, Markus; Nilsson, K Peter R; Sigurdson, Christina J.
in: J CLIN INVEST, Jahrgang 130, Nr. 3, 02.03.2020, S. 1350-1362.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease
AU - Sevillano, Alejandro M
AU - Aguilar-Calvo, Patricia
AU - Kurt, Timothy D
AU - Lawrence, Jessica A
AU - Soldau, Katrin
AU - Nam, Thu H
AU - Schumann, Taylor
AU - Pizzo, Donald P
AU - Nyström, Sofie
AU - Choudhury, Biswa
AU - Altmeppen, Hermann
AU - Esko, Jeffrey D
AU - Glatzel, Markus
AU - Nilsson, K Peter R
AU - Sigurdson, Christina J
PY - 2020/3/2
Y1 - 2020/3/2
N2 - 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.
AB - 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.
U2 - 10.1172/JCI131564
DO - 10.1172/JCI131564
M3 - SCORING: Journal article
C2 - 31985492
VL - 130
SP - 1350
EP - 1362
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 3
ER -