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 compound has previously been used in clinical trials for cancer and eye conditions in the United States, and a trial in Parkinson's Disease 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, although the form now used by scientists is a safer, synthetic analogue. To date, it has been extensively investigated as a potential anti-infective and anticancer therapy.

But in the new study, researchers discovered that squalamine also dramatically inhibits the early formation of toxic aggregates of the protein alpha-synuclein - a process thought to start a chain reaction of molecular events eventually leading to Parkinson's Disease. Remarkably, they also then found that it can suppress the toxicity of these poisonous particles.

The researchers tested squalamine in both cell cultures in the lab, and in an animal model using nematode worms. While their findings therefore only represent a step towards a treatment for Parkinson's Disease in humans, they described the results as representing significant progress. 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. 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 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.

Finally, the group tested the impact of squalamine in an animal model of Parkinson's Disease, by using nematode worms genetically programmed to over-express alpha-synuclein in their muscle cells. As the worms develop, alpha-synuclein aggregation causes them to become paralysed, 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.

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 main molecular processes determining Parkinson's Disease take place.

The researchers suggest that it would be particularly interesting to start investigating the efficacy of squalamine as a means to alleviate certain symptoms. If taken orally, for instance, the compound may perhaps relieve the severe constipation many patients experience, by targeting the gastrointestinal system and affecting alpha-synuclein in the gut. It is also conceivable that a treatment of that sort could "cascade" signals to other parts of the body.  

http://www.joh.cam.ac.uk/natural-compound-can-block-formation-toxins-associated-parkinson%E2%80%99s-disease