Mechanism for Prions’ Spread Between Species Identified

Prions are infectious proteins involved in transmissible spongiform encephalopathies (TSEs) or “prion disease,” which results in various symptoms related to neurodegeneration. Some diseases include Creuzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (mad cow disease) in cattle, and chronic wasting disease in deer and elk. Transmission of these misfolded proteins is one of the most elusive parts of this complicated disease, and researchers at Case Western Reserve University School of Medicine uncovered a mechanism for how prions can jump between some animal species but not others.  

“One of the major remaining questions in the field of prion diseases has been why these diseases are transmissible between some animal species but not others,” says Witold Surewicz, senior author and professor in the Department of Physiology and Biophysics at the School of Medicine. “Our findings explain how this works.”

The team’s work, published in the journal Nature Structural & Molecular Biology, began by examining the structure of prion protein fibrils linked to a hereditary form of human prion disease. Surewicz explains that misshapen protein assembles into long fibrils, acting as a template or “seed” to bind with a normal prion protein. The misshapen prion can then change the original protein’s shape into an abnormal, harmful form.

Previously, the Surewicz lab developed a model with a truncated form of prion proteins allowing them to study their mechanisms within test tubes. This allowed the researchers to assess the prion’s transmissibility barriers. Specifically, the team utilized high-resolution cryo-electron microscopy, where images are gathered at extremely low temperatures, for a better look at the infectious fibrils’ structures.

“It appears that the barriers—or lack thereof—are fully dictated by the ability of prion protein from one species to adopt the structure of prion fibril seeds from another species,” says Qiuye Li, lead author and postdoctoral fellow at the School of Medicine. “This, in turn, depends on differences in amino acid at key structure-determining positions.”

The researchers analyzed thousands of images of fibrils on human and mouse prion proteins at an incredibly finite scale, with a resolution close to individual atoms. This allowed them to deduce how prions can jump between certain species, but not all.

“Even though our present studies were performed using a model system,” Surewicz says, “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 among elk and deer in parts of the United States and Canada, and growing concerns regarding potential transmission of this disease to humans.”