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Molecular biology and pathology of prion strains in sporadic human prion diseases

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Abstract

Prion diseases are believed to propagate by the mechanism involving self-perpetuating conformational conversion of the normal form of the prion protein, PrPC, to the misfolded, pathogenic state, PrPSc. One of the most intriguing aspects of these disorders is the phenomenon of prion strains. It is believed that strain properties are fully encoded in distinct conformations of PrPSc. Strains are of practical relevance to human prion diseases as their diversity may explain the unusual heterogeneity of these disorders. The first insight into the molecular mechanisms underlying heterogeneity of human prion diseases was provided by the observation that two distinct disease phenotypes and their associated PrPSc conformers co-distribute with distinct PrP genotypes as determined by the methionine/valine polymorphism at codon 129 of the PrP gene. Subsequent studies identified six possible combinations of the three genotypes (determined by the polymorphic codon 129) and two common PrPSc conformers (named types 1 and 2) as the major determinants of the phenotype in sporadic human prion diseases. This scenario implies that each 129 genotype–PrPSc type combination would be associated with a distinct disease phenotype and prion strain. However, notable exceptions have been found. For example, two genotype–PrPSc type combinations are linked to the same phenotype, and conversely, the same combination was found to be associated with two distinct phenotypes. Furthermore, in some cases, PrPSc conformers naturally associated with distinct phenotypes appear, upon transmission, to lose their phenotype-determining strain characteristics. Currently it seems safe to assume that typical sporadic prion diseases are associated with at least six distinct prion strains. However, the intrinsic characteristics that distinguish at least four of these strains remain to be identified.

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Acknowledgments

We are grateful to Dr. Jiri Safar for the critical reading of the manuscript. This research was supported by the National Institutes of Health (NIH) grants AG14359 (to P.G., Q.K. and W.K.S.), AG08702 (to P.G.), NS062787 (to W.Q.Z.), NS44158 (to W.K.S.), NS38604 (to W.K.S.); the Centers for Disease Control and Prevention grant CCU 515004 (to P.G.); the Britton Fund; CJD Foundation, Alliance BioSecure and the University Center on Aging and Health with the support of the McGregor Foundation and the President’s Discretionary Fund (Case Western Reserve University to W.Q.Z.).

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  1. Department of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH, 44106, USA

    Pierluigi Gambetti, Ignazio Cali, Silvio Notari, Qingzhong Kong & Wen-Quan Zou

  2. Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA

    Witold K. Surewicz

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  1. Pierluigi Gambetti
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Correspondence to Pierluigi Gambetti.

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Gambetti, P., Cali, I., Notari, S. et al. Molecular biology and pathology of prion strains in sporadic human prion diseases. Acta Neuropathol 121, 79–90 (2011). https://doi.org/10.1007/s00401-010-0761-3

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