NEW STUDY PROVIDES INSIGHTS INTO TRANSMISSION OF MAD COW AND OTHER PRION DISEASES
24 January 2007 - Case Western Reserve University

These misshaped proteins, that clump together to form large particles known as amyloids, are believed to replicate by binding to the normal form of prion proteins and forcing them to convert to the abnormal form.

Despite growing evidence, the protein-only hypothesis is still far from being universally accepted, creating one of the longest lasting controversies in modern biology. The main argument made by some scientists against the protein-only hypothesis has to do with the existence of different strains of prion causing clinically distinct diseases. For these scientists, there cannot be various strains of proteins and, thus, there must be as yet undiscovered prion-specific nucleic acids producing the variations in strains within the same species of mammals. Another challenge, the one of great practical importance, is to understand factors that control barriers in transmission of prion diseases between different species of mammals such as, for example, sheep and cows or cows and humans.

Now a new study published by Case Western Reserve University researchers has clearly ruled in favor of the protein-only model. Their findings demonstrate that the ability to form different strains is an inherent property of prion protein amyloids, and that prion strains and species barriers in fact represent different sides of the same coin. Furthermore, they describe the mechanism that allows prions from one species to change the shape of proteins even from different species and thus cross the transmissibility barrier. The paper, coauthored by Eric Jones, a graduate student in the Case Department of Physiology and Biophysics, and Witold Surewicz, Ph.D., professor of physiology and biophysics, appears in April 8 issue of Cell.

The study examined abnormal prion particles formed in a test tube by prion proteins from various mammalian species. Using nano-scale imaging by a technique known as atomic force microscopy, the researchers revealed that the three-dimensional shape (or conformation) of prion particles varies considerably between proteins from different species. Spectroscopic techniques showed that the structural differences persist down to the atomic level.

Importantly, the Case team demonstrated the molecular shape controls the ability of prions from one species to initiate (or “seed”) the conversion to an abnormal form of protein from another species. While the cross-species seeding between proteins that form abnormal prion particles with similar shape is very effective, considerable barriers usually exist for cross-seeding between prions that show preferences for different conformations. However, the researchers also found that, under some circumstances, prion proteins from one species can be made to take on the molecular shape and, by virtue of that, the seeding properties of another. Whether this happens or not, depends on “conformational compatibility” of prion protein from two different species, that is, whether the protein from one species can adapt its shape to match that of the protein from the other species.

“For example,” said Surewicz, “when mouse prion proteins were exposed to very small amounts of abnormal hamster prion particles, the resulting mouse prions no longer formed structures characteristic of mouse proteins, but rather adopted the shape of the template hamster prions. As a result of this altered conformation, mouse prions lost their original seeding specificity, acquiring that of hamster prions. In other words, a “hamster-like‚” strain of mouse prions was formed.”

In addition to demonstrating that prion strains and species barriers can be fully explained within the confines of the protein-only model, the finding that prions from one species can adopt the molecular shape and seeding properties of another has major practical implications. In particular, the study explains, at the molecular level, how variant Creutzfeldt-Jakob disease might have emerged as a new strain of human prion resulting from contact with and “conformational adaptation” to bovine prions. Furthermore, the finding that prion protein can be “forced” into any of several strains by cross-seeding with structurally compatible prions from different species raises an unsettling possibility that, in principle, prions could cross essentially any species barriers by gradual conformational adaptation resulting from repeated cross-infection events through intermediate species.

“In light of the past epidemics of mad cow disease, and emerging chronic wasting disease in North American deer and elk, this issue of cross-species prion transmission has become a critical public health concern in the United States and elsewhere,” said Surewicz.

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