title: Heparin binding confers prion stability and impairs its aggregation.
abstract: The conversion of the prion protein (PrP) into scrapie PrP (PrP(Sc)) is a central event in prion diseases. Several molecules work as cofactors in the conversion process, including glycosaminoglycans (GAGs). GAGs exhibit a paradoxical effect, as they convert PrP into protease-resistant PrP (PrP-res) but also exert protective activity. We compared the stability and aggregation propensity of PrP and the heparin-PrP complex through the application of different in vitro aggregation approaches, including real-time quaking-induced conversion (RT-QuIC). Transmissible spongiform encephalopathy-associated forms from mouse and hamster brain homogenates were used to seed RT-QuIC-induced fibrillization. In our study, interaction between heparin and cellular PrP (PrP(C)) increased thermal PrP stability, leading to an 8-fold decrease in temperature-induced aggregation. The interaction of low-molecular-weight heparin (LMWHep) with the PrP N- or C-terminal domain affected not only the extent of PrP fibrillization but also its kinetics, lowering the reaction rate constant from 1.04 to 0.29 s(-1) and increasing the lag phase from 12 to 19 h in RT-QuIC experiments. Our findings explain the protective effect of heparin in different models of prion and prion-like neurodegenerative diseases and establish the groundwork for the development of therapeutic strategies based on GAGs.
authors.affiliation: Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Instituto de Bioquímica Médica Leopoldo De Meis, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, and jerson@bioqmed.ufrj.br tuane@bioqmed.ufrj.br.
authors.forename: Tuane C R G
authors.initials: TC
authors.lastname: Vieira
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and.
authors.forename: Yraima
authors.initials: Y
authors.lastname: Cordeiro
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Hamilton, Montana, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
authors.affiliation: Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Instituto de Bioquímica Médica Leopoldo De Meis, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, and jerson@bioqmed.ufrj.br tuane@bioqmed.ufrj.br.
authors.forename: Jerson L
authors.initials: JL
authors.lastname: Silva
mesh_terms: D000682:Amyloid / Q000096:biosynthesis; D000818:Animals; D006224:Cricetinae; D006493:Heparin; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000737:chemistry*; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects
chemical_list: D000682:Amyloid; D006495:Heparin, Low-Molecular-Weight; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D006493:Heparin
keywords: glycosaminoglycan; neurodegeneration