2. Academic Validation
  3. Spontaneous generation of diverse recombinant prion strains: sulfated glycan cofactors facilitate strain emergence but do not determine specific strain properties

Spontaneous generation of diverse recombinant prion strains: sulfated glycan cofactors facilitate strain emergence but do not determine specific strain properties

  • Acta Neuropathol Commun. 2025 Dec 3;13(1):249. doi: 10.1186/s40478-025-02175-w.
Nuria L Lorenzo # 1,  Hasier Eraña # 2 3 4,  Enric Vidal 5 6,  Jorge M Charco 2 3 4,  Lucía Parga 1,  Carlos M Díaz-Domínguez 2,  Sonia Veiga 1,  Susana Bravo 7,  Samanta Giler 5 6,  Mariví Geijo 8,  Jesús R Requena 9,  Joaquín Castilla 10 11 12
Affiliations

Affiliations

  • 1 CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain.
  • 2 Prion Research Lab, CIC BioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain.
  • 3 Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain.
  • 4 ATLAS Molecular Pharma S. L, Derio, Spain.
  • 5 Unitat mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Bellaterra, Catalonia, Spain.
  • 6 IRTA. Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Universitat Autònoma de Barcelona (UAB), Campus, Bellaterra, Catalonia, Spain.
  • 7 Proteomics Unit, Instituto de Investigaciones Sanitarias de Santiago (IDIS), Santiago de Compostela, Spain.
  • 8 Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development , Basque Research and Technology Alliance (BRTA), Derio, Spain.
  • 9 CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain. [email protected].
  • 10 Prion Research Lab, CIC BioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain. [email protected].
  • 11 Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain. [email protected].
  • 12 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. [email protected].
  • # Contributed equally.
PMID: 41340161 DOI: 10.1186/s40478-025-02175-w
Abstract

Significant advances over the last two decades in the study of in vitro prion formation and propagation have revealed that distinct cofactors can facilitate or induce spontaneous prion misfolding. This, in turn, has raised important questions about the role of cofactors and their potential significance in vivo in prion diseases. Key questions include whether cofactors are necessary for prion infectivity or whether they might play a crucial role in determining strain features without being essential for Infection. Grounded in previous work that showed that polyanions such as RNA or dextran sulfate facilitate spontaneous prion misfolding in vitro, we have addressed whether Other chemically similar cofactors could expand the diversity of PrPSc conformers and whether these would exhibit distinctive strain features. Using the Protein Misfolding Shaking Amplification (PMSA) and three different polyanionic cofactors (heparin, chondroitin sulfate and pentosan polysulfate), we obtained and characterized a total of nine conformers and compared them to previously generated strains obtained with dextran sulfate. All nine conformers proved infectious in transgenic mice, generating distinct prion strains and suggesting that different cofactors can indeed drive the formation of distinct conformers. However, the observed variations within conformers generated with the same cofactor indicate a degree of structural flexibility, likely resulting in related but distinguishable groups of conformers. Our study demonstrates that sulfated glycans not only facilitate in vitro spontaneous PrPSc generation but also enable the emergence of multiple distinct prion strains, providing insights into the molecular mechanisms underlying strain diversity and their potential relevance to spontaneous prion diseases.

Keywords

Cofactors; PMSA; PrPSc; Prion diseases; Prion strains; Recombinant prions; Spontaneous misfolding; Spontaneous prions; Strain diversity; Sulfated glycans.

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