A team of scientists has generated high-resolution 3D images of dangerous prions, building on a 30-year-old project, and is expected to offer insights into how prions assemble and behave.

The new study involved researchers from the National Institutes of Health's (NIH) National Institute of Allergy and Infectious Diseases (NIAID) in Montana and the Case Western Reserve University in Ohio. Researchers were able to create the medical imaging breakthrough by using cryo-electron microscopy. 

Structure of a Major Prion Protein
(Photo: PoopAcidMaker via Wikimedia Commons)

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The new images also mark the first atomic-level observations on prions. These are pathogenic proteins that trigger normal proteins in the body to fold abnormally, leading to often fatal neurodegenerative diseases in both animals and humans. With the new imaging results, researchers hope to guide future efforts on addressing diseases caused by prions.

"These detailed prion structures provide a new premise for understanding and targeting these currently untreatable diseases," says Allis Kraus, Ph.D., the lead and co-corresponding author of the study and an assistant professor at the Case Western Reserve School of Medicine's pathology department in a report from Genetic Engineering & Biotechnology News (GEN). She adds that it will be easier to develop and test hypotheses regarding the assembly of prions with medical imaging breakthroughs.

A Breakthrough from a 30-Year-Old NIAID Project

A report from NIAID explains that the quest to understand the molecular of the pathogenic proteins began 30 years before, with Kraus' mentor, Byron Caughey, Ph.D. The long-running project has seen countless research team members come and go, with a series of contributions building up to the final piece found by the researchers in the latest study.

At the center of the 30-year-old project are prions, which are corrupted proteins that cause prion diseases. With the medical imaging results of prions now available, researchers believe that this will provide colleagues with a basis for understanding how normal prions refold and accumulate to cause adverse effects to the host.

Before the medical imaging breakthrough, scientists only had educated guesses about the molecular structure of these pathogenic proteins to guide efforts in developing therapies, procedures, and medications against prion diseases. From these hypotheses, a pair of theories emerged as the most commonly accepted. The first is that the protein structure is a stack of corkscrew-like molecules known as the beta-solenoid model. The other one builds on the proposal made by Caughey's team in 2014: the parallel-in-register intermolecular beta-sheet (PIRIBS), where prion molecules are stacked like pancakes to form fibrils. The images from the new study confirm that the second one is correct.

Utilizing Cryo-Electron Microscopy to Lead a Medical Imaging Discovery

In the study "High-Resolution Structure and Strain Comparison of Infectious Mammalian Prions," published in the Molecular Cell journal, August 25, researchers explain that the cryo-electron microscopy revealed a PIRIBS structure for an infectious brain-derived prion.

The prions in the medical imaging effort were taken from rodent-adapted scrapie prions from the brains of hamsters determined to be clinically ill. Researchers used cryo-EM equipment at the NIH and the Cleveland Center for Structural and Membrane Biology Cryo-Electron Microscopy Core - both at Case Western Reserve.

To take the high-resolution 3D images, researchers suspended the prions in ice before subjecting them to cryo-EM and building 3D atomic-resolution models with the help of proprietary software.


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