Transgenic over-expression of mammalian heparanase delays prion disease onset and progression

Ben-Zaken, Olga; Nissan, Israel; Tzaban, Salit; Taraboulos, Albert; Zcharia, Eyal; Matzger, S.; Shafat, Itay; Vlodavsky, Israël; Tal, Yuval

doi:10.1016/j.bbrc.2015.06.170

Cited by 6 publications

(1 citation statement)

References 44 publications

(77 reference statements)

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“…Moreover, polyanions administered intraventricularly increase survival time in experimental rodent models and in patients, potentially by blocking prion binding to endogenous HS [ 33 – 44 ]. Additionally, transgenic expression of mammalian heparanase, an enzyme that degrades HS, was reported to delay prion disease onset and progression [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection

Aguilar-Calvo,

Malik,

Sandoval

et al. 2023

PLoS Pathog

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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.

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Section: Introductionmentioning

confidence: 99%

Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection

Aguilar-Calvo,

Malik,

Sandoval

et al. 2023

PLoS Pathog

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Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions

et al. 2019

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Heparan Sulfate and Heparin Promote Faithful Prion Replication in Vitro by Binding to Normal and Abnormal Prion Proteins in Protein Misfolding Cyclic Amplification

Imamura

Tabeta

Kato

et al. 2016

Journal of Biological Chemistry

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Edited by Paul FraserThe precise mechanism underlying the conversion of normal prion protein ( Sc by using a modified PMCA performed with baculovirusderived recombinant PrP (Bac-PrP) as a substrate. The addition of heparan sulfate (HS) or its analog heparin (HP) restored the conversion efficiency in PMCA that was inhibited through nucleic acid depletion. Moreover, the PMCA products obtained under these conditions were infectious and preserved the properties of the input PrP Sc . These data suggest that HS and HP play the same role as nucleic acids in facilitating faithful replication of prions in PMCA. Furthermore, we showed that HP binds to both Bac-PrP and Bac-PrP Sc through the sulfated groups present on HP and that the N-terminal domain of Bac-PrP Sc might potentially not be involved in the binding to HP. These results suggest that the interaction of GAGs such as HS and HP with PrP C and/or PrP Sc through their sulfate groups is critical for the faithful replication of prions.

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Transgenic over-expression of mammalian heparanase delays prion disease onset and progression

Cited by 6 publications

References 44 publications

Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection

Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection

Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions

Heparan Sulfate and Heparin Promote Faithful Prion Replication in Vitro by Binding to Normal and Abnormal Prion Proteins in Protein Misfolding Cyclic Amplification

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