The findings of this study were published in the journal ‘Journal of Molecular Biology’.
Professor Jody Mason, from the Department of Biology and Biochemistry at the University of Bath, who was in charge of the research, stated, “Although much more work needs to be done, this molecule has the potential to be used as a drug precursor in the future. Currently, there are only medications available to treat the symptoms of Parkinson’s disease; however, we hope to develop a drug that will allow people to regain their health even before symptoms appear.”
Parkinson’s Disease is characterized by the’misfolding’ of a specific protein in human cells, resulting in the protein becoming aggregated and causing the cell to malfunction. The protein alpha-synuclein (aS) is found in high concentrations in all human brains. After misfolding, it accumulates in large masses known as Lewy bodies, which are toxic to the body. These masses are made up of aS aggregates, which are toxic to dopamine-producing brain cells and cause them to die as a result of their presence. It is this decrease in dopamine signaling that causes the symptoms of Parkinson’s Disease to manifest themselves, as the signals transmitting from the brain to the body become noisy, resulting in the distinctive tremors that are observed in patients with the condition.
Researchers had previously examined a large library of peptides (short chains of amino acids – the building blocks of proteins) in an attempt to find the best candidate for preventing aS misfolding and thereby halting neurodegeneration caused by the substance. According to previous research by scientists at the University of Bath, the peptide 4554W showed the most promise when it was tested in lab experiments in solutions and on live cells. Peptide 4554W prevented aS from aggregating and forming toxic disease forms in both solutions and live cells.
This same group of scientists has tweaked the peptide 4554W in order to improve its function in their most recent research. It was discovered that a new version of the molecule, 4654W(N6A), contained two modifications to the parental amino-acid sequence, and that it was significantly more effective at decreasing aS misfolding, aggregation, and toxicity. It is still many years away from finding a cure for the disease if the modified molecule continues to show promise in laboratory experiments.
Dr. Richard Meade, the study’s principal investigator, stated, “In the past, attempts to inhibit alpha-synuclein aggregation with small molecule drugs have been unsuccessful because the molecules are too small to interfere with such large protein interactions. peptides are a good alternative because they are large enough to prevent protein aggregation while still being small enough to be used as a drug delivery system. Because of the 4654W(N6A) peptide’s ability to inhibit alpha-synuclein aggregation and cell survival in cultured cells, it is very encouraging that we now know where to target the alpha-synuclein protein in order to reduce 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, which will aid in our understanding of why the protein misfolds in the first place, as well as the development of new diagnostic tools.”
Professor Mason went on to say, “Afterwards, we’ll be looking into how we can get this peptide into a clinical setting. We need to figure out how to further modify it so that it behaves more like a drug and can cross biological membranes to reach the cells of the brain. This may imply a shift away from naturally occurring amino acids and toward molecules that have been created in a laboratory setting.”
This research also has implications for Alzheimer’s disease, Type 2 diabetes, and other serious human diseases where symptoms are triggered by protein misfolding, such as Parkinson’s disease and vascular dementia.
“Finding ways to prevent 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,” said Dr Rosa Sancho, head of research at Alzheimer’s Research UK.
“We’re pleased to have contributed to this important research into the development of a molecule that can prevent alpha-synuclein from misfolding in the brain. The molecule has been tested in cells in the laboratory, but it will need to undergo additional development and testing before it can be used as a therapeutic agent on humans. This process will take several years, but it is a promising discovery that has the potential to pave the way for the development of a new drug in the future “Dr. Sancho went on to say more.
According to her, “At this time, there are no disease-modifying treatments available for Parkinson’s disease or dementia with Lewy bodies, which is why continued investment in research is so important for all those who are affected by these diseases.”