Squalamine, a naturally occurring compound studied for its anticancer and anti-infective properties, has been found to block a molecular process thought to cause Parkinson’s, and to suppress its toxic products, scientists have reported.

The findings, although only preliminary, suggest that the compound, squalamine, could be the basis of a potential treatment for Parkinson’s Disease and a trial in patients is now being planned by one of the researchers involved in the study.

Squalamine is a steroid which was discovered in the 1990s in dogfish sharks. The form used by scientists now is a safer and more reliable synthetic analogue. 

In the new study, researchers discovered that squalamine dramatically inhibits the early formation of toxic aggregates of the protein alpha-synuclein – a process thought to eventually leading to Parkinson's. Remarkably, they also then found that it can suppress the toxicity of these molecules.

The researchers stated that whilst their findings represent a step towards a treatment for Parkinson’s Disease in humans, they described the results as representing significant progress.

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.

Professor Christopher Dobson, who is one of the authors and Master of St John’s College, as well as a Professor in the Chemistry Department at the University of Cambridge, said:

To our surprise, we found evidence that squalamine not only slows down the formation of the toxins associated with Parkinson’s Disease, but also makes them less toxic altogether.
If further tests prove to be successful, it is possible that a drug treating at least some of the symptoms of Parkinson’s Disease could be developed from squalamine. We might then be able to improve on that incrementally, by searching for better molecules that augment its effects.

Professor Michele Vendruscolo, from the Department of Chemistry at the University of Cambridge and a co-author, said:

...if there are going to be ways to beat the disease, it seems likely that this is one that may work.

In the new study, the researchers explored squalamine’s capacity to displace alpha-synuclein from cell membranes. This finding has significant implications for Parkinson’s, 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 actually aids the flow of neurotransmitters, but in some instances, it malfunctions and instead begins to misfold and clump together, creating toxic particles harmful to neurons. This clumping is the hallmark of Parkinson’s Disease.

The researchers carried out a series of experiments which analysed 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.

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 and a clinical trial with squalamine in Parkinson’s is planned in patients in the US.

Further research is, however, needed to determine what the precise benefits of squalamine would be – and what form any resulting drug might take. In particular, it is not yet clear whether squalamine can reach the specific regions of the brain where the processes determining Parkinson’s take place.

The researchers do also suggest that it would be particularly interesting to start investigating the efficacy of squalamine as a means to alleviate certain Parkinson's symptoms. If taken orally, for instance, the compound may potentially relieve the severe constipation many patients experience, by targeting alpha-synuclein in the gut.

It is also conceivable that a treatment of that sort could “cascade” signals to other parts of the bodydand in some cases be sufficient to delay the progress of other aspects of Parkinson’s.

“In many ways squalamine gives us a lead rather than a definitive treatment,” Professor Dobson added. “Parkinson’s Disease has many symptoms and we hope that either this compound, or a derivative of it with a similar mechanism of action, could alleviate at least some of them.”

“One of the most exciting prospects is that, subject to further tests, we might be able to use it to make improvements to patients’ lives, while also studying other compounds with the aim of developing a more powerful treatment in the future.”

The Cure Parkinson's Trust is particularly interested in research which directly targets the toxic intermediates of protein aggregation, and our safety trial of the molecule Anle 138b (which like squalamine, modulates toxic oligomers of amyloidogenic proteins) in patients under our Linked Clinical Trials programme is due to start in 2018.

Why is alpha-synuclein of particular interest to CPT?

The paper 'A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity' is published in Proceedings of the National Academy of Sciences December 5 2016