The Generative Brain

PMSA, Protein Misfolding Shaking Amplification for generating bona fide recombinant prions

PMSA is a laboratory method, not a treatment or a test offered to anyone. It is a shaking-based variant of protein misfolding cyclic amplification, developed in the prion laboratory at CIC bioGUNE in Derio with co-authors from Atlas Molecular Pharma, that propagates and generates infectious prions from bacterially produced recombinant prion protein rather than from brain material. The first description, in PLoS Pathogens on 23 October 2019, presented it as a scalable way to make enough homogeneous recombinant prion material for high resolution structural work. A 2023 paper in Acta Neuropathologica Communications set out what drives the spontaneous formation of such prions using the method. The method was named PMSA in a Nature Communications paper of 8 March 2024, which applied it across more than 380 mammalian prion proteins and sorted them by how readily they misfold on their own and how variable the resulting conformations are. Since then the same group has used it to ask what role cofactors play in misfolding and in strain emergence, to study cervid prion protein variation, and to supply material to other laboratories working on prion biology and on candidate therapies. The entry is kept deliberately at the level of what the work is for and who does it. No procedural detail is recorded here, because the method produces infectious material and the atlas has no reason to hold a recipe. Information only, not medical advice.

Key facts

  • The founding paper is Erana and colleagues, Development of a new largely scalable in vitro prion propagation method for the production of infectious recombinant prions for high resolution structural studies, PLoS Pathogens volume 15 issue 10, article e1008117, first published 23 October 2019, open access, DOI 10.1371/journal.ppat.1008117, last author Castilla.
  • The repo ledger note on that record describes it as a shaking-based alternative to the sonication used in protein misfolding cyclic amplification, with a cofactor (dextran sulfate) that reduces structural heterogeneity so the product is uniform enough for structural methods such as solid state NMR.
  • The name Protein Misfolding Shaking Amplification appears with the paper Erana and colleagues, A Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions, Nature Communications volume 15, article 2112, first published 8 March 2024, open access, DOI 10.1038/s41467-024-46360-2.
  • That 2024 paper worked across more than 380 mammalian prion proteins and classified them by spontaneous misfolding propensity and by conformational variability; the institutional announcement covered in the search excerpts adds that the products were inoculated into highly susceptible animal models to confirm infectivity.
  • The intermediate step is Erana and colleagues, Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation, Acta Neuropathologica Communications volume 11, article 145, 7 September 2023.
  • The same approach underlies a prion decontamination evaluation method published as Erana and colleagues, A Novel, Reliable and Highly Versatile Method to Evaluate Different Prion Decontamination Procedures, Frontiers in Bioengineering and Biotechnology volume 8, article 589182, 29 October 2020; the repo ledger note records four Atlas Molecular Pharma affiliated authors and ERDF and Spanish ministry funding on it.
  • Two follow-on papers test what cofactors actually do: Perez-Castro and colleagues, Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions, PLoS Pathogens volume 21, e1012890, 22 January 2025; and Lorenzo and colleagues, Spontaneous generation of diverse recombinant prion strains: sulfated glycan cofactors facilitate strain emergence but do not determine specific strain properties, Acta Neuropathologica Communications volume 13, article 249, 3 December 2025.
  • A Europe PMC term search returned 43 records; after removing unrelated hits that matched the acronym by chance, every prion record using or citing the method has Castilla as last author and most have Erana as first or second author, with recurring co-author institutions at IRTA-CReSA, Colorado State University, CIMUS Santiago de Compostela, Istituto Superiore di Sanita and Neiker.
  • The method supplies material to work the atlas already tracks: the 2026 Neurobiology of Disease paper on the kuru-protective G127V variant as a dominant-negative strategy, led from the Harris laboratory, carries Erana and Castilla as co-authors, and the 2026 PNAS paper on prion protein unfolding during propagation carries the same two with CIMUS and Trento co-authors.
  • Related non-method output from the same group includes a 2025 PLoS Pathogens phylogeny of the mammalian PRNP gene and a 2025 Neurobiology of Disease study of cervid prion protein variation, both of which read as applications of the same cross-species misfolding question the 2024 paper opened.
  • This is distinct from the surface PMCA decontamination assay already in the atlas as dx-surf-pmca-decontamination, which uses brain derived material and belongs to a French transfusion service group, and from the diagnostic amplification assays (RT-QuIC, urine and plasma PMCA). PMSA is a production and modelling tool, not a diagnostic.

Timeline

  1. 2019PLoS Pathogens paper introduces the scalable shaking-based recombinant prion propagation method.
  2. 2020Review by the same group on PrPSc detection and the contribution of cell free amplification to prion diagnosis, Biomolecules volume 10, article 469.
  3. 2020Frontiers in Bioengineering and Biotechnology paper applies the approach to evaluating prion decontamination procedures.
  4. 2023Acta Neuropathologica Communications paper reports the methodology for swift and consistent spontaneous generation of bona fide prions.
  5. 2024Nature Communications paper names PMSA and applies it across more than 380 mammalian prion proteins.
  6. 2025PLoS Pathogens paper reports that cofactors help misfolding in vitro but are not required for infectivity of the recombinant murine product.
  7. 2025Acta Neuropathologica Communications paper reports that sulfated glycan cofactors facilitate strain emergence without determining strain properties.
  8. 2026Neurobiology of Disease paper on the G127V dominant-negative strategy, with CIC bioGUNE and Atlas co-authors.
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