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  • Aguilar-Calvo, PatriciaUniv Calif, CA 92093 USA (author)

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

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • 2019-10-31
  • SPRINGER,2020
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-164367
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-164367URI
  • https://doi.org/10.1007/s00401-019-02085-xDOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies|NCATS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1 TR001442]; NIAMS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R01 AR064202]; NIA NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [AG031189, R01 AG031189, AG061251, IL1 TR001442, K99 AG061251]; NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS069566, NS076896, NS103848]; NINDS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01 NS069566, R01 NS103848, R01 NS076896]
  • 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.

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  • Sevillano, Alejandro M.Univ Calif, CA 92093 USA (author)
  • Bapat, JaidevUniv Calif, CA 92093 USA (author)
  • Soldau, KatrinUniv Calif, CA 92093 USA (author)
  • Sandoval, Daniel R.Univ Calif, CA USA (author)
  • Altmeppen, Hermann C.Univ Med Ctr Hamburg, Germany (author)
  • Linsenmeier, LuiseUniv Med Ctr Hamburg, Germany (author)
  • Pizzo, Donald P.Univ Calif, CA 92093 USA (author)
  • Geschwind, Michael D.Univ Calif San Francisco, CA USA (author)
  • Sanchez, HenryUniv Calif San Francisco, CA USA (author)
  • Appleby, Brian S.Case w Reserve Univ, OH USA (author)
  • Cohen, Mark L.Case w Reserve Univ, OH USA (author)
  • Safar, Jiri G.Case w Reserve Univ, OH USA (author)
  • Edland, Steven D.Univ Calif, CA USA (author)
  • Glatzel, MarkusUniv Med Ctr Hamburg, Germany (author)
  • Nilsson, PeterLinköpings universitet,Kemi,Tekniska fakulteten(Swepub:liu)petni61 (author)
  • Esko, Jeffrey D.Univ Calif, CA USA (author)
  • Sigurdson, Christina J.Univ Calif, CA USA (author)
  • Univ Calif, CA 92093 USAUniv Calif, CA USA (creator_code:org_t)

Related titles

  • In:Acta Neuropathologica: SPRINGER139:3, s. 527-5460001-63221432-0533

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