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Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation.

Hasier ErañaCarlos M Díaz-DomínguezJorge M CharcoEnric VidalEzequiel González-MirandaMiguel A Pérez-CastroPatricia PiñeiroRafael López-MorenoCristina Sampedro-Torres-QuevedoLeire Fernández-VeigaJuan Tasis-GalarzaNuria L LorenzoAileen Santini-SantiagoMelisa LázaroSandra García-MartínezNuno Gonçalves-AnjoMaitena San-Juan-AnsoleagaJosu Galarza-AhumadaEva Fernández-MuñozSamanta GilerMikel ValleGlenn C TellingMariví GeijóJesús R RequenaJoaquín Castilla
Published in: Acta neuropathologica communications (2023)
Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt-Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous misfolding of the cellular PrP (PrP C ) into the pathogenic isoform (PrP Sc ). Currently, the molecular mechanisms that trigger and drive this event, which occurs in approximately one individual per million each year, remain completely unknown. Modelling this phenomenon in experimental settings is highly challenging due to its sporadic and rare occurrence. Previous attempts to model spontaneous prion misfolding in vitro have not been fully successful, as the spontaneous formation of prions is infrequent and stochastic, hindering the systematic study of the phenomenon. In this study, we present the first method that consistently induces spontaneous misfolding of recombinant PrP into bona fide prions within hours, providing unprecedented possibilities to investigate the mechanisms underlying sporadic prionopathies. By fine-tuning the Protein Misfolding Shaking Amplification method, which was initially developed to propagate recombinant prions, we have created a methodology that consistently produces spontaneously misfolded recombinant prions in 100% of the cases. Furthermore, this method gives rise to distinct strains and reveals the critical influence of charged surfaces in this process.
Keyphrases
  • late onset
  • platelet rich plasma
  • amyotrophic lateral sclerosis
  • escherichia coli
  • cell free
  • genome wide
  • small molecule