A new study has shone light on the molecular steps behind the spread of prion diseases, a group of incurable brain conditions that have puzzled researchers for decades.
Alzheimer’s disease wears down the aging brain like a slow process of coastal erosion. Prion diseases, in contrast, are a neurological tsunami. The events that proceed the wave of damage caused by these conditions are subtle, like a gentle ripple in the sea, far from shore.
Like Alzheimer’s, the most common versions of prion disease appear to be the result of a mix of genetic and environmental factors. Unlike Alzheimer’s, certain, rare prion diseases can be caused by infection with a prion protein. These diseases, such as variant Creutzfeldt-Jakob Disease (vCJD) or Kuru, can incubate for up to 40 years after first exposure, which often occurs through the consumption of contaminated meat.
After these benign decades, a torrent strikes. Once symptoms start, 70% of CJD patients are dead within a year. Researchers trying to peer through the dark waters of prion disease have now made a striking breakthrough, revealing the events that turn a harmless protein into an infectious pathogenic prion.
That breakthrough has come in a paper published in Proceedings of the National Academy of Sciences, led by researchers at Imperial College London and the University of Zurich. “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,” commented Alfonso De Simone, senior author of the study and a professor in the Department of Life Sciences at Imperial College London, in a press release.
Whilst the clinical signs of prion disease mimic that of Alzheimer’s, characterized by failing memory, visual alterations and changes to behaviour, the molecular events surrounding prion disease have long been mysterious, even though the culprit has been clearly identified. At disease onset, the human prion protein (PrP), a glycosylated, monomeric protein that links to the outer neuronal membrane, suddenly undergoes a Jekyll and Hyde-like transformation, undergoing an aberrant structural misfold that changes it into prion protein scrapie (PrPSc).
This twisted version of prion protein has shown what appears to be the ability to spread between neuronal cells and is prone to aggregation into amyloid fibrils, a process that sees the delicate neuronal proteome become gummed up with molecular mess, leading to rapid degeneration.
Picking apart what provokes this rapid and lethal transformation of PrP has been the grand challenge of prion research, and De Simone and colleagues believe they have made serious strides towards overcoming it.
Tracking a molecular “ghost”
Previous research had identified several pathological mutations that seemed to stimulate regions of PrP into misfolding. One of these, a mutation commonly found both in patients with very early-onset dementia and prion disease, is called T183A, denoting a single amino acid change from threonine to alanine.
The team studied T183A in detail, showing how the mutation led to a destabilization of the PrP protein structure. Their biggest innovation was the use of nuclear magnetic resonance spectroscopy (NMR) to study the intermediate protein structure that T183A induces, one that exists in a limbo between the benign PrP and the pathological PrPSc. This structure, as study lead author Dr Máximo Sanz-Hernández explains, has proved incredibly hard to pin down: “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.”
By revealing this structure, the two teams were then able to design antibodies that could target the conformational change involved. In a simple test tube proof-of-concept study, the team were able to halt prions from morphing into their diseased structure.
The next stage of the work will be refining the antibody into something that can be introduced into the brain – the current version is too large to make it past the blood-brain barrier. The team hope that the target they have now painted on the prion mechanism will allow other teams to pore through their library of compounds for existing drugs or molecules that could act as a therapy.
For Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, who helped fund the research, the way forward is clear: “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.”