NIAID Study Reveals, Compares Prion Strains

NIAID Now | July 13, 2022

The top image shows a hamster prion; the lower image a mouse prion. These cross-sectional “mugshots” of prion strains show their overall structural similarities, but also their many different details. Each provides a distinct template for prion growth.

Credit: Graphic by Bryan Hansen, NIAID

NIAID Study Reveals, Compares Prion Strains

Prions are infectious protein pathogens that cause fatal neurodegenerative diseases in mammals. For decades, scientists have wondered how different strains of prions can propagate when they do not carry their own genes with them as they move from host to host. A new study from NIAID researchers and colleagues at Case Western Reserve University in Cleveland reveals – in near-atomic detail – how differences in the folding of the primary protein of prions (PrP) can help determine the distinct characteristics of prion strains.

The research teams are pursuing studies of prion structure to aid in the design and screening of treatments that might slow or prevent the spread of these deadly diseases. Prion diseases are caused by the corruption of the normal form of PrP that is made by all mammals. Although poorly understood, normal PrP molecules spend most of their time as individual units that play roles in multiple physiological functions.

Rarely, and for unknown reasons, normal PrP molecules can spontaneously refold into highly structured assemblies that cause brain disease. This spontaneous process seems to be responsible for the most common form of prion disease in humans, sporadic Creutzfeldt-Jakob disease. However, once formed, corrupted PrP aggregates, or prions, can be highly infectious if inadvertently transferred from one person to another by invasive medical procedures. In other mammals with poorer basic hygiene, such as livestock and wildlife, prion infections such as scrapie, chronic wasting disease, or mad cow disease can spread by more casual contact and contaminate the environment.

Multiple strains of prions have been identified in all these host species, with each giving a distinctive array of clinical presentations, molecular features, patterns of damage in the brain, and transmissibility to other species. Thus, deciphering the basis of prion strain diversity is important in understanding the risks posed by prions to which humans or animals are exposed.

Prions can reproduce in hosts a billion times or more during infection. They do so without having their own infection-specific genes because all PrP molecules are encoded by the same host gene. For this reason, scientists cannot easily track prions like they can viruses and bacteria.

The new study, published in Nature Communications, comes from the same researchers who in 2021 published the first high-resolution structure of an infectious prion protein. That work solved the structure of a specific hamster-adapted strain of scrapie, a prion disease that occurs naturally in sheep and goats. The initial study also reported lower resolution images of a mouse-adapted form of scrapie that already indicated strain-dependent differences in overall shape. 

The latest study uses cryo-electron microscopy to show the structure of this mouse-adapted second prion strain in much greater detail. The strain was depicted at a resolution of about 3 angstroms in size (1 angstrom is equal to one hundred-millionth of a centimeter). Comparing these rodent prion strains reveals that, although they share some key structural similarities, their details greatly differ overall.

Importantly, both strains are pancake-like layers of PrP molecules with a ladder-like protein substructure. Prior to the 2021 study, scientists only had educated guesses to guide their work regarding prion characteristics.

“The structural basis for how prions replicate as deadly pathogens, and to do so consistently as different strains to cause distinct diseases, has long been a major mystery in our field of research,” Dr. Byron Caughey, the senior NIAID scientist on the study, said. “Now we have a much clearer idea of how this works – at least for these first two strains that we have solved so far.”

References:
F Hoyt et al. Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains. Nature Communications. DOI: https://doi.org/10.1038/s41467-022-30458-6 (2022).

A Kraus et al. High-resolution structure and strain comparison of infectious mammalian prions. Molecular Cell. DOI: 10.1016/j.molcel.2021.08.011. (2021).

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