Unique, but how? Probing atomic-scale diversity among prions with electrons

Prions are infectious agents that cause fatal brain diseases, such as bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. They consist of misshapen forms of one of the body's own proteins called the prion protein (PrP) stacked together in the form of rods. Once formed in the body, prion rods act as seeds to convert normal PrP into a likeness of themselves, setting off a chain reaction leading to progressive accumulation throughout the brain. This accumulation triggers changes in the brain that cause nerve cells to die leading to severe dementia and ultimately death.

Prion rods grow by incorporating PrP to their ends and spread by breaking into smaller pieces to produce new 'seeds'. So far, the exact structures of these prion rods have been unknown: how PrP is misshapen has been a key question, arousing various speculations.

Even more puzzling, prions exhibit different strains that cause differing patterns of disease, similar to typical germs, such as bacteria or viruses. Unlike bacteria or viruses, prions have no DNA or RNA, which could provide disease-causing instructions specific for each strain. As prions are composed solely of protein, there has been a long-standing debate about how strains of prions can exist.

Recent work in the Unit using state-of-the-art electron cryo-microscopy (cryo-EM) with colleagues at Birkbeck College has now revealed the long-sought prion structures at near-atomic resolution and has shown that prion rods from distinct mouse prion strains, called ME7 and RML, are built from distinctly folded chains of PrP. The structure of the RML prion fibril is published at Nature Communications and the ME7 structure published at Nature Chemical Biology, with its detailed side-by-side comparison with the RML structure.

Zooming into atomic details of prion rods

Cryo-EM demonstrated that PrP chains, the basic building blocks of prion rods, are arranged in a parallel manner, forming something of a twisted ribbon, with each PrP forming a single rung spanning the full width of that ribbon (Fig. 1). This type of arrangement is characteristic for so-called amyloid fibrils.

Fig. 1. Structural diversity among mouse prion fibrils.

It has become clear that since consecutive PrP chains are added at the tips of growing rods, the shape or fold of the chain at that tip moulds the incoming PrP into the same shape and stabilises it through very strong chemical bonds, producing so-called b-sheets between the rungs (illustrated by arrows in Fig. 1), otherwise known as the cross-b structure. This is how the uniform shape of the whole fibril is maintained, enabling seeded spread of a given prion strain. This is also possible due to the fact that PrP can adopt many different folds.

Future outlook

The methods we established to reveal structural differences among mouse prion strains can now be applied to explore similarities between different human and animal prion strains. Overall we aim to establish a comprehensive structure-based classification system and use this to evaluate which existing or newly emerging animal prion strains might pose a threat to humans. This new information should have direct translation to protecting public health.