How do prions jump from one species to another?

In a new study, researchers at case Western Reserve University School of Medicine have discovered a protein fibril structure

While their findings have no direct implications for developing new therapies for more common human prion diseases such as Creutzfeldt-Jakob disease, this work does show that the likelihood of

Witold Surewicz, senior author of the study and professor in the Department of Physiology and Biophysics at the Faculty of Medicine, said: "A major question that remains in the field of prion diseases is why these diseases can spread between some animal species and not between others

The study, funded by the National Institutes of Health, was published Sept.

Prion disease, also known as "infectious spongiform encephalopathy", is a group of infectious brain-depleting diseases, including human kernic disease, bovine spongiform encephalopathy (mad cow disease), and chronic attenuated diseases

These deadly diseases are unique because their infectious agent is not a virus, but an unusually shaped prion protein

Surevich said the malformed protein assembles long fibers and binds to normal prion proteins in the form of templates or "seeds," forcing it to change shape into an abnormal, disease-causing form

While abnormally shaped proteins can easily be transformed as templates for normal prion proteins from the same species, cross-seeding is thought to be limited by species-dependent amino acid sequence differences, which are a fundamental building block

"It seems that these barriers — or lack thereof — are entirely determined

Previously, scientists in Surewicz's lab developed a model using truncated forms of prion proteins that allowed them to study the mechanisms of prion transmission, including the phenomenon

However, due to the lack of information on the structure of the infectious fibrillary fibers formed by these proteins, adequate understanding of these mechanisms is hampered

The authors overcome this fundamental limitation by using cryo-electron microscopy techniques

By analyzing thousands of images of fibrils formed by prion proteins in human and mouse models in a computer, they determined the structure

"Although our current study was conducted using a model system," Surewicz said, "the ability to rationalize and predict the prion transmission barrier based on structural data has important practical implications, especially given the chronic wasting disease currently prevalent in elk and deer in parts of the United States and Canada, and the growing concern that the disease may be transmitted to humans

essay

Cryo-EM structure of disease-related prion fibrils provides insights into seeding barriers