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Prion protein glyca...
Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease
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- Sevillano, Alejandro M. (author)
- UCSD, CA USA; Univ Texas MD Anderson Canc Ctr, TX 77030 USA
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- Aguilar-Calvo, Patricia (author)
- UCSD, CA USA
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- Kurt, Timothy D. (author)
- UCSD, CA USA; Fdn Food and Agr Res, DC USA
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- Lawrence, Jessica A. (author)
- UCSD, CA USA
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- Soldau, Katrin (author)
- UCSD, CA USA
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- Nam, Thu H. (author)
- UCSD, CA USA
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- Schumann, Taylor (author)
- UCSD, CA USA
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- Pizzo, Donald P. (author)
- UCSD, CA USA
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- Nyström, Sofie (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Choudhury, Biswa (author)
- UCSD, CA USA
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- Altmeppen, Hermann (author)
- Univ Med Ctr Hamburg Eppendorf, Germany
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- Esko, Jeffrey D. (author)
- UCSD, CA USA
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- Glatzel, Markus (author)
- USD, CA USA
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- Nilsson, Peter (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Sigurdson, Christina J. (author)
- UCSD, CA USA
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(creator_code:org_t)
- AMER SOC CLINICAL INVESTIGATION INC, 2020
- 2020
- English.
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In: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 130:3, s. 1350-1362
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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(1)(80Q)(/196Q)), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease.Prnp(1)(80Q)(/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(1)(80Q/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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Andra medicinska och farmaceutiska grundvetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Other Basic Medicine (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sevillano, Aleja ...
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Aguilar-Calvo, P ...
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Kurt, Timothy D.
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Lawrence, Jessic ...
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Soldau, Katrin
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Nam, Thu H.
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show more...
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Schumann, Taylor
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Pizzo, Donald P.
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Nyström, Sofie
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Choudhury, Biswa
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Altmeppen, Herma ...
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Esko, Jeffrey D.
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Glatzel, Markus
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Nilsson, Peter
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Sigurdson, Chris ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Other Basic Medi ...
- Articles in the publication
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Journal of Clini ...
- By the university
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Linköping University