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

  • Patricia Aguilar-Calvo
  • Alejandro M. Sevillano
  • Jaidev Bapat
  • Katrin Soldau
  • Daniel R. Sandoval
  • Hermann C. Altmeppen
  • Luise Linsenmeier
  • Donald P. Pizzo
  • Michael D. Geschwind
  • Henry Sanchez
  • Brian S. Appleby
  • Mark L. Cohen
  • Jiri G. Safar
  • Steven D. Edland
  • Markus Glatzel
  • K. Peter R. Nilsson
  • Jeffrey D. Esko
  • Christina J. SigurdsonEmail author
Original Paper


Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1+/) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography–mass spectrometry (LC–MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC–MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.


Amyloid Neurodegeneration Glycosaminoglycans ADAM10 cleavage 



We thank Chrissa Dwyer and Jessica Lawrence for discussions, Biswa Choudhury, Nazilla Alderson, and Jin Wang for outstanding technical support, and the animal care staff at UC San Diego for excellent animal care. We also thank the UC San Diego GlycoAnalytics Core for the mass spectrometry analysis. The authors are grateful to the patients’ families, the CJD Foundation, referring clinicians, and all the members of the National Prion Disease Pathology Surveillance Center for invaluable technical help. This study was supported by the National Institutes of Health grants NS069566 (CJS), NS076896 (CJS), NS103848 (JGS), AG031189 (MDG), AG061251 (PAC), IL1 TR001442 (SDE) the U.S. Centers for Disease Control and Prevention (BSA), the CJD Foundation (CJS and HCA), the Werner-Otto-Stiftung (HCA) the Michael J. Homer Family Fund (MDG), and the Ramón Areces Foundation (PAC).

Author contributions

PAC, KPRN, CJS, DRS, and JDE designed experiments, PAC, AMS, JB, KS, DPP, and KPRN performed the experiments, PAC, JB, LL, HCA, SDE, MG, JGS, KPRN, JDE, CJS, MLC, and BSA analyzed experiments, MDG and HS provided sCJD cases, and PAC and CJS wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.

Supplementary material

401_2019_2085_MOESM1_ESM.pdf (13 kb)
Bound to PrPSc (PDF 13 kb)
401_2019_2085_MOESM2_ESM.docx (15 kb)
Supplementary material 2 (DOCX 16 kb)
401_2019_2085_MOESM3_ESM.pdf (913 kb)
Online resource 1 Shortening heparan sulfate chains does not alter PrPC expression. a Western blot shows PrPC in brain homogenate of age-matched Ext1+/+ versus Ext1+/- mice and tga20+/-Ext1+/+ versus tga20+/-Ext1+/- mice (n=3/group) (anti-PrP antibody: POM19). b Quantification of PrPC levels relative to actin
401_2019_2085_MOESM4_ESM.pdf (843 kb)
Online resource 2 Shortening heparan sulfate chains does not impact the levels of PrPSc in brain. a Western blot shows PrPSc in brain homogenate of Ext1+/+ versus Ext1+/- mice (anti-PrP antibody: POM19). b Quantification of PrPSc levels (n=4-6/group)
401_2019_2085_MOESM5_ESM.pdf (785 kb)
Online resource 3 Immunolabeling for PrP and Alcian blue staining for acidic polysaccharides in the brain of prion-infected mice. Subfibrillar prions 22L, RML, and ME7 do not bind detectable levels of Alcian blue, while fibrillar prions mCWD and GPI- RML bind abundant Alcian blue, indicating the presence of acidic polysaccharides, such as GAGs. Shown is hippocampus (22L, RML, ME7, and GPI- RML) and corpus callosum (mCWD). Scale bar = 100 μm for 22L, RML, ME7, and mCWD, and 200 μm for GPI- RML
401_2019_2085_MOESM6_ESM.pdf (161 kb)
Online resource 4 mCWD plaque distribution in tga20+/-Ext1+/- and tga20+/-Ext1+/- mouse brains. aTga20+/-Ext1+/+ (Ext1+/+) and tga20+/-Ext1+/- (Ext1+/-) mice show similar plaque distribution in hippocampus (HP), thalamus (TH), hypothalamus (HT), basal ganglia (BG) and cortex (CX). bExt1+/- mice with survival times longer than 260 dpi (filled bars) show more plaques in the hippocampus and thalamus than the Ext1+/- mice with the shorter survival times (white bars) (n=10-13 mice/group). **P< 0.01 and ***P< 0.001, Fisher’s exact test
401_2019_2085_MOESM7_ESM.pdf (820 kb)
Online resource 5 PrPSc from the 22L-infected brain is composed of primarily GPI-anchored PrP and low levels of shed PrP. a Immunoblots of brain from mCWD- and 22L-infected mice labeled with POM19 antibody (discontinuous epitope at C-terminal domain, amino acids 201–225 of the mouse PrP) or sPrPG228 antibody (binds shed PrP) reveal low levels of sPrPG228 binding to 22L prions as compared to mCWD prions. b Ratios of ADAM10-cleaved PrPSc relative to total PrPSc reveal significantly lower levels of cleaved PrPSc in the 22L-infected brain as compared to mCWD-infected brain (more than 20-fold lower) [22L: 28 ± 18 (n=14) and mCWD: 630 ± 919 (n=5) (mean ± SE)]. *P< 0.05, Wilcoxon rank sum test (panel b)
401_2019_2085_MOESM8_ESM.pdf (541 kb)
Online resource 6 Silver staining of purified PrPSc for HS analysis
401_2019_2085_MOESM9_ESM.pdf (2.9 mb)
Online resource 7 Representative images of the brain histopathology from the human GSS and sCJD cases. GSS-F198S case: Frontal cortex sections immunolabeled for PrP reveal multicentric plaques. The HE stained section shows a little to no spongiform change. GSS-P102L case: Frontal cortex shows synaptic PrP deposits with fine, full-thickness spongiform degeneration (HE). sCJD cases: Brain at thalamus shows highly variable lesions associated with differences in the PRNP genotype at polymorphic codon 129. The sCJD 129 MM1 case shows diffuse or “synaptic” PrP deposits and intense fine vacuoles. The sCJD 129 MV2 case shows plaque-like deposits and vacuolar change, and the sCJD 129 VV2 case shows small plaques and moderate vacuolation. Inset shows MV2 and VV2 plaques from a different field at high magnification. Scale bars = 100 μm (GSS-F198S and sCJD), 10 μm (GSS-P102L) and 50 μm (insets)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Patricia Aguilar-Calvo
    • 1
  • Alejandro M. Sevillano
    • 1
  • Jaidev Bapat
    • 1
  • Katrin Soldau
    • 1
  • Daniel R. Sandoval
    • 2
  • Hermann C. Altmeppen
    • 3
  • Luise Linsenmeier
    • 3
  • Donald P. Pizzo
    • 1
  • Michael D. Geschwind
    • 4
  • Henry Sanchez
    • 4
  • Brian S. Appleby
    • 5
    • 6
  • Mark L. Cohen
    • 5
    • 6
  • Jiri G. Safar
    • 5
    • 6
  • Steven D. Edland
    • 7
    • 8
  • Markus Glatzel
    • 3
  • K. Peter R. Nilsson
    • 9
  • Jeffrey D. Esko
    • 2
  • Christina J. Sigurdson
    • 1
    • 10
    • 11
    Email author
  1. 1.Department of PathologyUniversity of California, San Diego (UCSD)La JollaUSA
  2. 2.Department of Cellular and Molecular MedicineUniversity of California, San Diego (UCSD)La JollaUSA
  3. 3.Institute of NeuropathologyUniversity Medical Center Hamburg-Eppendorf (UKE)HamburgGermany
  4. 4.Department of Neurology, Memory and Aging CenterUniversity of California, San Francisco (UCSF)San FranciscoUSA
  5. 5.Departments of Pathology and NeurologyCase Western Reserve UniversityClevelandUSA
  6. 6.National Prion Disease Pathology Surveillance CenterCase Western Reserve UniversityClevelandUSA
  7. 7.Department of Family Medicine and Public HealthUniversity of California, San Diego (UCSD)La JollaUSA
  8. 8.Department of NeurosciencesUniversity of California, San Diego (UCSD)La JollaUSA
  9. 9.Department of Physics, Chemistry, and BiologyLinköping UniversityLinköpingSweden
  10. 10.Department of MedicineUniversity of California, San Diego (UCSD)La JollaUSA
  11. 11.Department of Pathology, Immunology, and MicrobiologyUniversity of California, Davis (UCD)DavisUSA

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