Calcium fragment 39/9/2023 ![]() ![]() PrP C-PrP Sc conversion, physiologically prevented by energy barrier, can occur as a spontaneous stochastic event, possibly favored by mutations in the PrP gene ( PRNP) or acquired by infection with exogenous PrP Sc molecules. PrP Sc is considered the main, if not the solely, component of the prion, the infectious entity of TSE. According to the “protein only” hypothesis, TSE share a common pathogenic event: the posttranslational misfolding of a membrane-anchored glycoprotein (cellular prion protein, PrP C) into a protease-resistant, aggregation-prone isoform (PrP Sc). From a neuropathology point of view TSE are characterized by cerebral spongiform degeneration, loss of neurons and gliosis, often associated with amyloid deposition. TSE are invariably fatal, with death occurring frequently in less than 1 year after the first symptoms appear. ![]() In fact, in past years the appearance of a new variant of CJD, associated to the consumption of bovine spongiform encephalopathy-contaminated beef, created a troubling new scenario in the transmission of prion diseases. The epidemic nature of TSE in domestic and wild animals constitutes a serious health problem also for humans. Prion diseases, also called transmissible spongiform encephalopathy (TSE), are fatal neurodegenerative disorders of humans and animals characterized by sporadic, inherited and infective (transmissible) aetiology, including, among the human diseases, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease, fatal familial insomnia and kuru. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: Funding was provided by the Italian Ministry of University and Research: PRIN 2007 to Mazzanti, PRIN 2007 to Schininà, PRIN 2008 to Florio, FIRB 2011 to Florio. Received: JanuAccepted: Published: July 11, 2012Ĭopyright: © 2012 Sorrentino et al. Baskakov, University of Maryland, United States of America (2012) Calcium Binding Promotes Prion Protein Fragment 90–231 Conformational Change toward a Membrane Destabilizing and Cytotoxic Structure. Finally, by in silico structural analysis, we propose that Ca ++ binding to hPrP 90–231 modifies amino acid orientation, in the same way induced by E200K mutation, thus suggesting a pathway for the structural alterations responsible of PrP neurotoxicity.Ĭitation: Sorrentino S, Bucciarelli T, Corsaro A, Tosatto A, Thellung S, Villa V, et al. These features, either acquired after controlled thermal denaturation or induced by D202N and E200K mutations were previously identified as responsible for hPrP 90–231 cytotoxicity. We also report that Ca ++ binding to hPrP 90–231 induces a conformational change based on an alteration of secondary structure characterized by loss of alpha-helix content causing hydrophobic amino acid exposure and proteinase K resistance. A similar correlation between increased membrane conductance and cell degeneration has been observed assaying hPrP 90–231 bearing pathogenic mutations (D202N and E200K). Furthermore we show the existence of a direct link between these two effects as demonstrated by a highly statistically significant correlation in several experimental conditions. In the present study we demonstrate that hPrP 90–231, pre-incubated with 10 mM Ca ++ and then re-suspended in physiological external solution increases not only membrane conductance but neurotoxicity as well. We previously showed that the human PrP fragment 90–231 (hPrP 90–231) increases ionic conductance across artificial lipid bilayer, in a calcium-dependent manner, producing an alteration similar to that observed for PrP Sc. PrP Sc extracted from infected Syrian hamster brains induces a considerable change in membrane ionic conductance, although the contribution of this interaction to the molecular mechanism of neurodegeneration process is still controversial. The pathological form of prion protein (PrP Sc), as other amyloidogenic proteins, causes a marked increase of membrane permeability. ![]()
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