A molecule that shows promise in preventing Parkinson’s disease has been refined by scientists at the University of Bath and has the potential to be developed into a drug to treat the incurable neurodegenerative disease.
Parkinson’s disease is characterised by a specific protein in human cells ‘misfolding’, where it becomes aggregated and malfunctions. The protein – alpha-synuclein (αS) – is abundant in all human brains. After misfolding, it accumulates in large masses, known as Lewy bodies. These masses consist of αS aggregates that are toxic to dopamine-producing brain cells, causing them to die. It is this drop in dopamine signalling that triggers the symptoms of Parkinson’s, as the signals transmitting from the brain to the body become noisy, leading to the distinctive tremors seen in sufferers.
Previous efforts to target and ‘detoxify’ αS-induced neurodegeneration have seen scientists analyse a vast library of peptides (short chains of amino acids – the building blocks of proteins) to find the best candidate for preventing αS misfolding. Of the 209,952 peptides screened in earlier work by scientists at Bath, peptide 4554W showed the most promise, inhibiting αS from aggregating into toxic disease forms in lab experiments, both in solutions and on live cells.
In their latest work, this same group of scientists tweaked peptide 4554W to optimise its function. The new version of the molecule – 4654W(N6A) – contains two modifications to the parental amino-acid sequence and has proven to be significantly more effective than its predecessor at reducing αS misfolding, aggregation and toxicity. However, even if the modified molecule continues to prove successful in lab experiments, a cure for the disease is still many years away.
Dr Richard Meade, the study lead author, said: “Previous attempts to inhibit alpha synuclein aggregation with small molecule drugs have been unfruitful as they are too small to inhibit such large protein interactions. This is why peptides are a good option – they are big enough to prevent the protein from aggregating but small enough to be used as a drug. The effectiveness of the 4654W(N6A) peptide on alpha synuclein aggregation and cell survival in cultures is very exciting, as it highlights that we now know where to target on the alpha synuclein protein to supress its toxicity. Not only will this research lead to the development of new treatments to prevent the disease, but it is also uncovering fundamental mechanisms of the disease itself, furthering our understanding of why the protein misfolds in the first place.”
Read full paper in the Journal of Molecular Biology.
Release date: 09 December 2021
Source: University of Bath