Image Source: University College London
Prions are a type of protein that are present on the membranes of many cells, which can cause proteins in the brain to fold abnormally leading to prion diseases. Prion diseases are rare progressive neurodegenerative diseases that include Creutzfeldt-Jakob disease (CJD), variably protease-sensitive prionopathy, Gerstmann-Sträussler-Scheinker disease (GSS), Fatal Familial Insomnia, and Kuru.
These rare diseases occur when the normal prion protein becomes abnormal, which causes it to clump in the brain. The accumulation of abnormal protein leads to brain damage. Relatively little is known about prion diseases, which are always fatal.
For many years, the cause of prion diseases was not known. Scientists searched for infectious agents that could be responsible for these diseases and determined that the agent they were looking contained no nucleic acids so was not bacterial or viral, as the agents were not susceptible to ultraviolet radiation which destroys nucleic acids. These agents were found to be susceptible to molecules that disrupted proteins, leading to the conclusion that they were mostly made of proteins found on the membranes of cells.
Evidence has since grown supporting the hypothesis that the diseases are caused by distorted proteins that can bind to other proteins of the same type and cause them to also change their configuration, but the mechanism involved was not known. If the mechanism involved is not known, it cannot be blocked.
Now, new research conducted by scientists at Imperial College London and the University of Zurich has revealed what causes prion proteins to become pathogenic and cause prion diseases. The researchers have also identified a way to stop the process, which could lead to treatments that could prevent prion diseases from progressing.
The University College London researchers studied a mutant prion protein found in individuals with inherited prion disease and used nuclear resonance spectroscopy and computational analysis and found an intermediate step between the mutant prion protein and its benign form, from which they were able to identify the mechanism involved in the prion configuration changes.
Researchers at the University of Zurich produced an antibody that stopped the prion protein from misfolding, which could potentially halt the progression of the disease. Unfortunately, the antibody cannot be used as a therapeutic tool as it is too large to pass through the brain, but the researchers have demonstrated that the abnormal folding can be blocked.
“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,” said lead researcher and UCL professor, Alfonso De Simone. “Now we know what we’re targeting, we know what features drugs need to have to stop prions becoming pathogenic.”
You can read more about the study in the paper – Mechanism of misfolding of the human prion protein revealed by a pathological mutation – which was recently published in the journal Proceedings of the National Academy of Sciences (PNAS) on March 15, 2021.