Researchers discover structure of protein fibrils linked to inherited form of human prion disease

In a new study, researchers from Case Western Reserve University School of Medicine have identified the structure of protein fibrils linked to an inherited form of human prion disease. This idea, they say, reveals the mechanism by which prions can hop between certain animal species, while maintaining a transmissibility barrier between other species.

Although their findings do not have immediate implications for the development of new therapies for more common human prion disorders such as Creutzfeldt-Jakob disease, the work suggests that the disease transmission potential of a species to another can be predicted based on structural information.

One of the main questions that remains in the field of prion diseases is why these diseases are transmissible between certain animal species but not others. Our findings explain how it works.”

Witold Surewicz, professor in the Department of Physiology and Biophysics at Case Western Reserve School of Medicine and lead author of the study

The study, funded by the National Institutes of Health, was published Sept. 12 in the scientific journal Nature Structural and Molecular Biology. Qiuye Li, a postdoctoral fellow in the School of Medicine, was the lead author. The study was co-authored by Christopher Jaroniec, professor of chemistry and biochemistry at Ohio State University.

Prion diseases, also known as “transmissible spongiform encephalopathies”, are a group of infectious brain wasting disorders that include, among others, Creuzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (mad cow disease ) in cattle and chronic wasting disease in deer. and elk.

These deadly diseases are unique because of their infectious pathogen, which is not a virus but an abnormal form of the prion protein.

This deformed protein assembles into long fibrils that propagate by acting as a template — or “seed” — that binds to the normal prion protein and forces it to change shape into an abnormal, pathogenic one, Surewicz said.

While abnormally shaped proteins can readily act as templates to convert normal prion proteins of the same species, cross-seeding is thought to be limited due to species-dependent differences in amino acid sequence; the basic building blocks of each protein.

“It appears that the barriers – or lack thereof – are entirely dictated by the ability of the prion protein from one species to adopt the seed structure of prion fibrils from another species,” Li said. in turn, depends on amino acid differences at key structure-determining positions.”

Previously, scientists at the Surewicz laboratory had developed a model using a truncated form of prion proteins to study the mechanisms of prion propagation in a test tube, including the phenomenon of transmissibility barriers (seeding).

However, the complete understanding of these mechanisms has been hampered by the lack of information regarding the structure of the infectious fibrils formed by these proteins.

The authors overcame this fundamental limitation through the use of a cryo-electron microscopy technique; a type of microscopy in which images are collected at very low temperatures.

By analyzing on the computer thousands of images of fibrils formed by human and murine model prion proteins, they determined the architecture of these fibrils at a resolution close to individual atoms. This structural idea allowed the researchers to explain, in precise structural terms, why barriers of prion transmissibility exist between some species while none of these barriers are observed between other species.

“Even though our current studies were performed using a model system,” Surewicz said, “the ability to rationalize and predict prion transmissibility barriers based on structural data has important practical implications, especially given the current epidemic of chronic wasting disease in elk and deer in parts of the United States and Canada, and growing concerns about the potential transmission of this disease to humans.”


Case Western Reserve University

Journal reference:

Li, Q. et al. (2022) Cryo-EM structure of disease-related prion fibrils provides insight into seeding barriers. Structural and molecular biology of nature.

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