CLEVELAND – Researchers at Case Western Reserve University School of Medicine have taken a major step towards understanding how abnormal prion proteins, the suspected cause of mad cow and related diseases, change shape to jump from one animal species to another. In test tube experiments, they were able to make human prion proteins exhibit characteristics of mouse prions or hamster prions through the substitution of either one or two amino acids. Furthermore, they describe how prions may overcome natural transmissibility barriers between two species of mammals. This may happen if prion proteins from one of these two species have been exposed to abnormal prions from a third species.
The Case team's findings are reported in the April 9 issue of Molecular Cell. The senior author of the study is Witold Surewicz, Ph.D., professor of physiology and biophysics at Case. It is co-authored by David Vanik, Ph.D., and Krystyna Surewicz, Ph.D.
The new study demonstrates that fundamental aspects of prion propagation in mammals, including the species barrier and strain diversity, can be reproduced in a test tube using a highly purified protein, a finding that provides a strong support for the hypothesis that mad cow disease and related disorders are caused by prion proteins only.
Prion diseases, also known as transmissible spongiform encephalopathies, are a group of infectious neurodegenerative disorders that include Creuzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (mad cow disease) in cattle, and chronic wasting disease in deer and elk. It is generally believed that the infectious agent responsible for these fatal diseases is not a virus, but an abnormally shaped form of the prion protein. This highly unusual pathogen is believed to propagate by acting as a template that binds to normal prion protein and forces it to change shape into an abnormal, pathogenic form.
"While abnormally shaped proteins can readily act as templates to convert normal prion proteins from the same species, cross-species seeding is believed to be highly restricted due to differences in the sequence of amino acids, the basic building blocks of each protein," said W. Surewicz.
However, in this study, the researchers took a truncated form of prion proteins from different species of mammals and found that, when normal protein from one species is brought into contact with a minute quantity of an abnormal prion from the second species, a new prion strain may emerge which adopts the seeding properties of prion from the second species.
"We saw that natural amino acid sequence-based barriers that prevent cross-seeding between two species, A and B for example, can be readily bypassed by an adaptation process that involves pre-seeding of protein A with an abnormal form of protein from a third species, C. This adaptation process leads to the emergence of a new strain of prion A. Remarkably, even though this new strain has amino acid sequence of protein A, it adopts the molecular shape and seeding specificity of protein from species C, and can now infect B, which it originally could not do" said Surewicz.
The issue of barriers for interspecies transmissibility of the prion agent first was brought to the public eye by the epidemics of mad cow disease in the United Kingdom and rapidly growing concerns that the disease may have been transmitted to humans by consumption of tainted beef products. The first case of mad cow disease in the United States, reported last year, is having a major impact on the beef industry with calls for widespread testing of cattle.
The findings by the Case team provide fundamentally important insights into extraordinarily perplexing problems of prion strains and species barriers. "This study does not solve the problem completely because the abnormal form of prion protein formed in the test tube has not yet been shown to be infectious in animals," W. Surewicz said. "However, the present findings for prion protein in mammals are conceptually similar to those recently reported by others for the propagation of prion-like agents in yeast. This striking similarity strongly suggests that the principle of strain adaptability described in this study is of general validity. This principle may explain some of the most puzzling observations regarding mammalian prion propagation, including that regarding different properties of classical human CJD prions and vCJD prions, a variant of Creutzfeldt-Jakob Disease believed to be acquired by infection of humans with bovine prions. The apparent ability of prion strains to adopt different seeding specificities and thus overcome natural species barriers has major implications for the assessment of risk factors for the transmission of animal prion diseases to humans."
The study was supported by funding from the National Institute of Neurological Disorders and Stroke.
The above post is reprinted from materials provided by Case Western Reserve University. Note: Materials may be edited for content and length.
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