Scientists can explain why normal proteins convert to pathogenic form and cause brain diseases, it was announced last night.
Researchers from Imperial College London, UK, and the University of Zurich, Switzerland, believe their findings could pave the way for new drugs to target prion diseases, such as Kuru, mad cow disease, Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia.
While the healthy version of prions and the pathogenic version have been characterised, the intermediate step, which sees healthy ones transform into the diseased ones, was unknown.
Writing in Proceedings of the National Academy of Sciences, the researchers say they have now isolated the intermediate step and determined the mechanism that turns normal prions into their diseased form.
Lead researcher Professor Alfonso De Simone, from the Department of Life Sciences at Imperial, said: “Prion diseases are aggressive and devastating, and currently there is no cure. 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. Now we know what we’re targeting, we know what features drugs need to have to stop prions becoming pathogenic.”
The team worked with a mutant form of the prion protein that is found in people with inherited prion diseases. The mutant form is more aggressive, which causes prions to transition faster to their pathogenic form.
They used nuclear magnetic resonance spectroscopy combined with computational analysis to determine the structure of the intermediate step, identifying the molecular mechanism at work when the prion misfolds.
The team at the University of Zurich then produced antibodies that could target the mechanism and in a proof-of-concept study in the test tube, they successfully blocked prions transitioning from the normal to the pathogenic form.
Lead study author Dr Máximo Sanz-Hernández said: “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.”
Dr Rosa Sancho, head of research at Alzheimer’s Research UK, which supported the research, added: “This is early-stage research examining the short protein fragments, which can be highly unstable, short lived, and notoriously difficult to study.
“As the UK’s leading dementia research charity, we are pleased to fund this sophisticated work using biophysical and computational approaches to better understand the role fragments like this play in the development of disease. To identify new ways to reduce or combat these protein fragments in human disease we need to see sustained investment in dementia research.”
The researchers hope the information will allow drug researchers and pharmaceutical companies to scan their libraries of drug compounds for formulations that might be able to block the mechanism.
PNAS 15 March 2021
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