Correspondence

Codon 129 genotype and new variant CJD

Prions are defined as proteinaceous infectious particles since they are solely composed of an aberrantly folded protein devoid of nucleic acids. These novel entities are responsible for a large but rare class of neurodegenerative disorders in animals and humans collectively defined as prion diseases. In humans, these disorders may have sporadic, genetic, or acquired etiology. The aberrantly folded protein is derived from the physiological cellular prion protein ubiquitously expressed in all tissues and particularly abundant in the central nervous system. Novel techniques for early detection of prions in affected animals and humans have been recently developed and tested. Currently, no cure is available for these fatal disorders.

Prions are defined as proteinaceous infectious particles solely composed of an aberrantly folded endogenous protein devoid of nucleic acids. These novel molecular entities are responsible for numerous but rare neurodegenerative disorders in animals and humans collectively defined as prion diseases. In humans these disorders may have sporadic, genetic or acquired etiology. The aberrantly folded protein is derived from the physiological cellular prion protein ubiquitously expressed in all tissues and particularly abundant in the central nervous system. The molecular mechanisms by which prion proteins convert into prions and accumulate in the nervous system are still elusive. Novel techniques for early detection of prions in affected animals and humans have been recently developed and tested. Currently no cure is available for these fatal disorders.

Prions are propagated in Saccharomyces cerevisiae with remarkable efficiency, yet we know little about the structural basis of sequence variations in the prion protein that support or prohibit propagation of the prion conformation. We show that certain single-amino-acid substitutions in the prion protein Sup35 impact negatively on the maintenance of the associated prion-based [PSI⁺] trait by combining in vivo phenotypic analysis with solution NMR structural studies. A clear correlation is observed between mutationally induced conformational differences in one of the oligopeptide repeats (R2) in the N terminus of Sup35 and the relative ability to propagate [PSI⁺]. Strikingly, substitution of one of a Gly-Gly pair with highly charged residues that significantly increase structural definition of R2 lead to a severe [PSI⁺] propagation defect. These findings offer a molecular explanation for the dominant-negative effects of such psi-no-more (PNM) mutations and demonstrate directly the importance of localized structural definition in prion propagation.

A key event in prion diseases is the conversion of the prion protein (PrP) from its native α-helical conformation to a misfolded, β-sheet rich conformation. Thus, preventing or reversing PrP misfolding could provide a means to disrupt prion disease progression and transmission. However, determining the structure of misfolded PrP has been notoriously difficult due to its inherent heterogeneity and aggregation behavior. For these reasons, simplified peptide fragments have been used as models that recapitulate characteristics of full-length PrP, such as amyloid-like aggregation and fibril formation, and in vitro toxicity. We provide a biochemical and structural comparison of PrP(127–147) peptides from elk, bovine and hamster using electrophysiology, electron microscopy and fluorescence. Our results demonstrate that the PrP(127–147) peptides adopt distinct populations of fibril structures. In addition, the elk PrP(127–147) peptide is unique in its ability to enhance Thioflavin T fluorescence and its ability to modulate neuronal ion channel conductances.

Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt–Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea.

Background: A polymorphism in position 129 in the human prion protein modulates susceptibility to prion infection and disease phenotype.

Results: Mutations to various amino acids highlights the importance of position 129 during amyloid fibrillation.

Conclusion: Position 129 is a key site for early intermolecular interactions during fibrillation.

Significance: Insight into early mechanisms of aggregation implicates a means to prevent fibrillation.