Prion diseases occur when normal prion protein, found on the surface of many cells, becomes abnormal and clumps in the brain, causing brain damage. Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare progressive neurodegenerative disorders that affect both humans and animals. They are distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response. Unfortunately, prion diseases are usually rapidly progressive and always fatal. Human prion disease include Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia, and Kuru.

Now, researchers from Imperial College London and the University of Zurich report they have determined what causes normal proteins to convert to a disease form. They also report they have found a way to block the process, which may lead to new therapeutics.

Their findings are published in the Proceedings of the National Academy of Sciences (PNAS) in a paper titled, “Mechanism of misfolding of the human prion protein revealed by a pathological mutation.”

“Discovering the mechanism by which prions become pathogenic is a crucial step in one day tackling these diseases, as it allows us to search for new drugs,” explained lead researcher and professor Alfonso De Simone, from the department of life sciences at Imperial College London. “Now we know what we’re targeting, we know what features drugs need to have to stop prions becoming pathogenic.”

Prion protein (PrP) misfolding is a key part of the disease process. Proteins fold into 3D shapes that cause disease. The researchers used a mutant form of the prion protein that is found in people with inherited prion diseases as a model for observation.

Using nuclear resonance spectroscopy combined with computational analysis, the researchers were able to locate the structure of the intermediate step to reveal the molecular mechanism behind prion misfolding.

The structure of normal and mutant PrP proteins. [Imperial College London]
The researchers from the University of Zurich were able to produce antibodies that could target the mechanism. Currently, the antibodies are too large to pass into the brain, but the findings show promise for blocking the mechanism and will lead to the development of new therapeutics.

“The intermediate stage of prion pathogenesis is so transient it’s like a ghost—almost impossible to image. But now we have a picture of what we’re dealing with, we can design more specific interventions that can one day potentially control these devastating diseases.”

The researchers hope their discovery will help drug researchers and pharma companies pinpoint drug compounds that can block the mechanism and pass through the brain.