Dubbed the ‘zombie protein’, infectious prions wreak havoc in the brain and lead to fatal neurodegenerative diseases, such as mad cow disease. Now, researchers have taken the highest-ever resolution image of a prion and gathered atomic-level data about how they can kill.
“These detailed prion structures provide a new premise for understanding and targeting these currently untreatable diseases,” says Allison Kraus of the Case Western Reserve University, US, and lead author of the paper, published in Molecular Cell. “It will now be much easier to develop and test hypotheses about how prions are assembled as highly infectious and deadly protein structures.”
Prions are proteins in the brain that fold into the wrong shape, causing damage. Unlike other proteins, this misfolding is infectious, causing other proteins to also fold incorrectly. They are particularly nasty because they can also be transmitted between people or animals.
Read more: Alzheimer’s kills neurons that keep us awake
The team of researchers used cryogenic-electron microscopy to determine the basic building blocks of prions in the brains of clinically ill hamsters.
They found that the infectious prion fibrils – thin fibres comprised of aggregated proteins – were made of identical corrupted proteins stacked on top of each other, forming ‘rungs’. The fibrils were huge aggregates of corrupted proteins that were highly stable but non-functional, and resistant to disposal by other cell mechanisms.
When non-functional proteins build up in a cell, it disrupts other cellular functions by getting in the way, and this can lead to cell death.
The team also captured low-resolution images of another prion strain and found there were slight structural differences.
“It’s thought that there are many variations in prion structures as they relate to different diseases,” says Kraus. “Higher-resolution images provide clarity to many aspects of the cause and progression of these infectious diseases that are uniquely caused in nature by proteins, not viruses or bacteria.”
The authors hope the new structures will reveal novel targets for therapies that prevent infectious misfolding.