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Neuronal Ndst1 depl...
Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection
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- Aguilar-Calvo, Patricia (author)
- Univ Calif San Diego, CA 92093 USA; Pfizer, CA USA
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- Malik, Adela (author)
- Univ Calif San Diego, CA 92093 USA; Fate Therapeut, CA USA
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- Sandoval, Daniel R. (author)
- Univ Calif San Diego, CA USA; GSK plc, PA USA
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- Barback, Christopher (author)
- Univ Calif San Diego, CA USA; Univ Colorado, CO USA
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- Orru, Christina D. (author)
- NIAID, MT USA
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- Standke, Heidi G. (author)
- Case Western Reserve Univ, OH USA
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- Thomas, Olivia R. (author)
- Case Western Reserve Univ, OH USA
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- Dwyer, Chrissa A. (author)
- Univ Calif San Diego, CA USA
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- Pizzo, Donald P. (author)
- Univ Calif San Diego, CA 92093 USA
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- Bapat, Jaidev (author)
- Univ Calif San Diego, CA 92093 USA
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- Soldau, Katrin (author)
- Univ Calif San Diego, CA 92093 USA
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- Ogawa, Ryotaro (author)
- Univ Calif San Diego, CA USA
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- Riley, Mckenzie B. (author)
- Univ Alabama Birmingham, AL USA
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- Nilsson, Peter (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Kraus, Allison (author)
- Case Western Reserve Univ, OH USA
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- Caughey, Byron (author)
- NIAID, MT USA
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- Iliff, Jeffrey J. (author)
- VA Puget Sound Hlth Care Syst, WA USA; Univ Washington, WA USA
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- Vera, David R. (author)
- Univ Calif San Diego, CA USA
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- Esko, Jeffrey D. (author)
- Univ Calif San Diego, CA USA
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- Sigurdson, Christina J. (author)
- Univ Calif San Diego, CA 92093 USA; UC San Diego Hlth, CA 92093 USA; Bristol Myers Squibb, CA USA
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(creator_code:org_t)
- PUBLIC LIBRARY SCIENCE, 2023
- 2023
- English.
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In: PLoS Pathogens. - : PUBLIC LIBRARY SCIENCE. - 1553-7366 .- 1553-7374. ; 19:9
- Related links:
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase), from neurons or astrocytes, we then investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, only affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance. Prions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain of affected individuals triggering neuronal loss and neuroinflammation, yet the molecules that facilitate prion protein aggregation are largely unknown. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated, neuron-derived HS, and infect mice with different prions strains. We find that mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to controls. We also found that recombinant prion protein was efficiently transported within the interstitial fluid of mice having poorly sulfated HS, suggesting more efficient clearance from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates a specific HS biosynthetic enzyme to target to enhance protein clearance.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Aguilar-Calvo, P ...
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Malik, Adela
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Sandoval, Daniel ...
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Barback, Christo ...
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Orru, Christina ...
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Standke, Heidi G ...
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show more...
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Thomas, Olivia R ...
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Dwyer, Chrissa A ...
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Pizzo, Donald P.
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Bapat, Jaidev
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Soldau, Katrin
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Ogawa, Ryotaro
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Riley, Mckenzie ...
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Nilsson, Peter
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Kraus, Allison
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Caughey, Byron
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Iliff, Jeffrey J ...
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Vera, David R.
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Esko, Jeffrey D.
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Sigurdson, Chris ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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PLoS Pathogens
- By the university
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Linköping University