A naturally-occurring compound has been found to block a molecular process thought to underlie Parkinson’s Disease and to suppress its toxic products, scientists have reported. The findings, although only preliminary, suggest that the compound, called squalamine, could be exploited in various ways as the basis of a potential treatment for Parkinson’s Disease.
The study was led by academics from the Centre for Misfolding Diseases, based in the Chemistry Department at the University of Cambridge in the United Kingdom, and Georgetown University and the National Institutes of Health in the United States. Scientists from the Netherlands, Italy, and Spain also played key roles. The findings are published in Proceedings of The National Academy of Sciences.
In the new study, the researchers explored squalamine’s capacity to displace alpha-synuclein from cell membranes – a phenomenon that was first observed in the laboratory headed by another co-author, Dr. Ad Bax, in the National Institutes of Health in Bethesda, USA. This finding has significant implications for Parkinson’s Disease because alpha-synuclein works by binding to the membranes of tiny, bubble-like structures called synaptic vesicles, which help to transfer neurotransmitters between neurons.
Under normal circumstances, the protein thus aids the effective flow of chemical signals, but in some instances, it malfunctions and instead begins to clump together, creating toxic particles harmful to brain cells. This clustering is the hallmark of Parkinson’s Disease.
The researchers carried out a series of experiments which analyzed the interaction between squalamine, alpha-synuclein and lipid vesicles, building on earlier work from Cambridge scientists which showed the vital role that vesicles play in initiating the aggregation. They found that squalamine inhibits the aggregation of the protein by competing for binding sites on the surfaces of synthetic vesicles. By displacing the protein in this way, it significantly reduces the rate at which toxic particles form. Further tests, carried out with human neuronal cells, then revealed another key factor – that squalamine also suppresses the toxicity of these particles.
Finally, the group tested the impact of squalamine in an animal model of Parkinson’s Disease, by using nematode worms genetically programmed to overexpress alpha-synuclein in their muscle cells. As the worms develop, alpha-synuclein aggregation causes them to become paralyzed, but squalamine prevented the paralysis from taking effect.
Together, the results imply that squalamine could be used as the basis of a treatment targeting at least some of the symptoms of Parkinson’s Disease. Researchers are now planning a clinical trial with squalamine in Parkinson’s Disease patients in the US.
Citation: Michele Perni, Céline Galvagnion, Alexander Maltsev, Georg Meisl, Martin B. D. Müller, Pavan K. Challa, Julius B. Kirkegaard, Patrick Flagmeier, Samuel I. A. Cohen, Roberta Cascella, Serene W. Chen, Ryan Limboker, Pietro Sormanni, Gabriella T. Heller, Francesco A. Aprile, Nunilo Cremades, Cristina Cecchi, Fabrizio Chiti, Ellen A. A. Nollen, Tuomas P. J. Knowles, Michele Vendruscolo, Adriaan Bax, Michael Zasloff, and Christopher M. Dobson. “A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity.” PNAS 2017
Adapted from press release by University of Cambridge.