Misfolding alpha-synuclein (αS) proteins are considered key players in the development of Parkinson's disease, giving rise to toxic clumps called Lewy bodies that kill off important brain cells. As such, a lot of research focuses on preventing this type of protein dysfunction, and scientists at the University of Bath have now made a breakthrough with the development of a finely engineered peptide, which produced "very exciting" results in early experiments.
Lewy bodies are associated with a range of neurological diseases, but their role in the onset of Parkinson's is tied to their tendency to kill neurons that produce the neurotransmitter dopamine. The death of these cells and decline in dopamine is what drives the deterioration of motor control seen in Parkinson's sufferers, such as tremors and slowness of movement.
The development of drugs that intervene in this process by targeting αS is a highly active area of research, and one where scientists are making some promising strides. Recent advances in the space include molecules that help the brain seek and destroy the misfolding proteins, molecular tweezers that can pull the clumps apart, and artificial enzymes that prevent them from spreading.
The University of Bath team has been pursuing a peptide-based solution to this problem, screening more than 200,000 of the chains of amino acids in search of one that can prevent αS misfolding. This led them to a peptide called 4554W, which stopped αS from developing into toxic clumps in laboratory experiments on live cells.
“Previous attempts to inhibit αS aggregation with small molecule drugs have been unfruitful as they are too small to inhibit such large protein interactions," says Dr Richard Meade, the study lead author. "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 scientists have continued studying this peptide and working to improve its performance. They made two alterations to the parental amino-acid sequence to produce a new version, called 4654W(N6A), which they say is significantly more effective at preventing misfolding, aggregation and toxicity of αS. Critically, it does so in a way that reveals chinks in the protein's armor.
"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 suppress its toxicity," says Meade. "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.”
The research has implications not just for the treatment of Parkinson's disease, but also other neurological disease where misfolding proteins play a part. Lewy bodies are associated with various forms of dementia, so drugs that prevent them from forming could have wide-ranging consequences.
“Finding ways to stop alpha synuclein from becoming toxic and damaging brain cells could highlight a new pathway for future drugs to stop devastating diseases like Parkinson’s and dementia with Lewy bodies," says Dr Rosa Sancho, head of research at Alzheimer’s Research UK. “We’re pleased to have supported this important work to develop a molecule that can stop alpha synuclein from misfolding. The molecule has been tested in cells in the laboratory and will need further development and testing before it can be made into a treatment. This process will take a number of years, but it is a promising discovery that could pave the way for a new drug in future."
The research was published in the Journal of Molecular Biology.
Source: University of Bath
