MedicalResearch.com Interview with:
Romolo Nonno, DVM, PhD
Istituto Superiore di Sanità
Dipartimento di Sanità Pubblica Veterinaria e Sicurezza Alimentare
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Previous studies have suggested that prion populations are composed of a variety of conformational variants subjected to Darwinian evolution driven by selective regimes. However, the exact molecular mechanisms that make prions able to self-replicate and mutate are still poorly understood.
A major technical advance in this field has been the discovery of techniques that allow to replicate prions in vitro, outside live organisms. One of these techniques, Protein Misfolding Cyclic Amplification (PMCA), allows to grow prion populations for a very high number of replications in a relatively short time period.
Furthermore it is conceivable that the in vitro environment offers less constraint to prion replication than live animals or cells, due to the absence of active clearance and cell division, which are key players of conformers selection in ex vivo models. These features make PMCA an attractive tool to investigate prion replication, mutation and evolution. By using PMCA, we investigated the in vitro evolution of prion populations derived from natural scrapie. Unexpectedly, we found that the cloud of conformational variants which compose a natural scrapie isolate also includes “defective” variants which, once isolated, are unable to self-sustain in vivo.
Importantly, we found that the defective prion mutant that we have isolated possesses unique biochemical properties in that its prion domain lacks the central region of prion protein, which is invariably present in known infectious mammalian prions.
MedicalResearch.com: What should readers take away from your report?
Response: That not all self-propagating prion protein aggregates are able to behave as deadly prions in vivo. This implies that some conformational variants of misfolded prion protein can be efficiently cleared by the infected organism. The existence of natural conformational variants able to self-replicate in vitro but not in vivo will hopefully contribute to find out the molecular mechanisms allowing misfolded prion protein conformers to become deadly prions.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Future studies should focus on the cellular mechanisms which block the in vivo replication of self-propagating prion protein aggregates lacking the central region of the prion protein in their protease-resistant core. These might include the active proteolytic processing of prion protein by endogenous proteases, whose roles in the physiological function of prion protein and on the pathological consequences of prions are still poorly understood. Our results also highlight the importance of the prion protein central domain in the auto-catalytic misfolding of prions, and future studies should focus on the role of this region in the infectivity of prions.
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Isolation of a Defective Prion Mutant from Natural Scrapie
Published: November 23, 2016
Ilaria Vanni,Sergio Migliore,Gian Mario Cosseddu,Michele Angelo Di Bari,Laura Pirisinu,Claudia D’Agostino,Geraldina Riccardi,Umberto Agrimi,Romolo Nonno
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