Synthetic Prion Selection and Adaptation

Edoardo Bistaffa, Fabio Moda, Tommaso Virgilio, Ilaria Campagnani, Chiara Maria Giulia De Luca, Martina Rossi, Giulia Salzano, Giorgio Giaccone, Fabrizio Tagliavini, Giuseppe Legname

Research output: Contribution to journalArticle

Abstract

Prion pathologies are characterized by the conformational conversion of the cellular prion protein (PrPC) into a pathological infectious isoform, known as PrPSc. The latter acquires different abnormal conformations, which are associated with specific pathological phenotypes. Recent evidence suggests that prions adapt their conformation to changes in the context of replication. This phenomenon is known as either prion selection or adaptation, where distinct conformations of PrPSc with higher propensity to propagate in the new environment prevail over the others. Here, we show that a synthetically generated prion isolate, previously subjected to protein misfolding cyclic amplification (PMCA) and then injected in animals, is able to change its biochemical and biophysical properties according to the context of replication. In particular, in second transmission passage in vivo, two different prion isolates were found: one characterized by a predominance of the monoglycosylated band (PrPSc-M) and the other characterized by a predominance of the diglycosylated one (PrPSc-D). Neuropathological, biochemical, and biophysical assays confirmed that these PrPSc possess distinctive characteristics. Finally, PMCA analysis of PrPSc-M and PrPSc-D generated PrPSc (PrPSc-PMCA) whose biophysical properties were different from those of both inocula, suggesting that PMCA selectively amplified a third PrPSc isolate. Taken together, these results indicate that the context of replication plays a pivotal role in either prion selection or adaptation. By exploiting the ability of PMCA to mimic the process of prion replication in vitro, it might be possible to assess how changes in the replication environment influence the phenomenon of prion selection and adaptation.

Original languageEnglish
JournalMolecular Neurobiology
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Prions
Proteins
PrPSc Proteins
Fourier Analysis
Protein Isoforms
Pathology
Phenotype

Keywords

  • Adaptation
  • PMCA
  • Prion
  • RT-QuIC
  • Selection
  • Synthetic prion

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Bistaffa, E., Moda, F., Virgilio, T., Campagnani, I., De Luca, C. M. G., Rossi, M., ... Legname, G. (Accepted/In press). Synthetic Prion Selection and Adaptation. Molecular Neurobiology. https://doi.org/10.1007/s12035-018-1279-2

Synthetic Prion Selection and Adaptation. / Bistaffa, Edoardo; Moda, Fabio; Virgilio, Tommaso; Campagnani, Ilaria; De Luca, Chiara Maria Giulia; Rossi, Martina; Salzano, Giulia; Giaccone, Giorgio; Tagliavini, Fabrizio; Legname, Giuseppe.

In: Molecular Neurobiology, 01.01.2018.

Research output: Contribution to journalArticle

Bistaffa, E, Moda, F, Virgilio, T, Campagnani, I, De Luca, CMG, Rossi, M, Salzano, G, Giaccone, G, Tagliavini, F & Legname, G 2018, 'Synthetic Prion Selection and Adaptation', Molecular Neurobiology. https://doi.org/10.1007/s12035-018-1279-2
Bistaffa E, Moda F, Virgilio T, Campagnani I, De Luca CMG, Rossi M et al. Synthetic Prion Selection and Adaptation. Molecular Neurobiology. 2018 Jan 1. https://doi.org/10.1007/s12035-018-1279-2
Bistaffa, Edoardo ; Moda, Fabio ; Virgilio, Tommaso ; Campagnani, Ilaria ; De Luca, Chiara Maria Giulia ; Rossi, Martina ; Salzano, Giulia ; Giaccone, Giorgio ; Tagliavini, Fabrizio ; Legname, Giuseppe. / Synthetic Prion Selection and Adaptation. In: Molecular Neurobiology. 2018.
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