In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 9 ( 2023-9-25), p. e1011487-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011487
DOI:
10.1371/journal.ppat.1011487.g001
DOI:
10.1371/journal.ppat.1011487.g002
DOI:
10.1371/journal.ppat.1011487.g003
DOI:
10.1371/journal.ppat.1011487.g004
DOI:
10.1371/journal.ppat.1011487.s001
DOI:
10.1371/journal.ppat.1011487.s002
DOI:
10.1371/journal.ppat.1011487.s003
DOI:
10.1371/journal.ppat.1011487.s004
DOI:
10.1371/journal.ppat.1011487.s005
DOI:
10.1371/journal.ppat.1011487.s006
DOI:
10.1371/journal.ppat.1011487.s007
DOI:
10.1371/journal.ppat.1011487.s008
DOI:
10.1371/journal.ppat.1011487.s009
DOI:
10.1371/journal.ppat.1011487.s010
DOI:
10.1371/journal.ppat.1011487.s011
DOI:
10.1371/journal.ppat.1011487.s012
DOI:
10.1371/journal.ppat.1011487.s013
DOI:
10.1371/journal.ppat.1011487.s014
DOI:
10.1371/journal.ppat.1011487.s015
DOI:
10.1371/journal.ppat.1011487.s016
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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