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Monday, January 16, 2017

Cambridge scientists make revolutionary discovery for Parkinson's Disease

January 16, 2017

Clinical trials are now being planned for Parkinson's Disease patients in the USA

Cambridge scientists have discovered a naturally-occurring steroid that could be used as the basis of a revolutionary treatment for Parkinson’s Disease.
Cambridge scientists have discovered a naturally-occurring steroid that could be used as the basis of a revolutionary treatment for Parkinson’s Disease. 
Preliminary findings show the compound squalamine blocks a molecular process thought to underlie the disease and suppresses its toxic products.
Cambridge scientists have discovered a naturally-occurring steroid that could be used as the basis of a revolutionary treatment for Parkinson’s Disease. 
Preliminary findings show the compound squalamine blocks a molecular process thought to underlie the disease and suppresses its toxic products.
The compound has previously been used in clinical trials for cancer and eye conditions in the USA, and a trial in Parkinson’s Disease patients is now being planned in the US in the near future.
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.
Since then 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.
And they also then found that it can suppress the toxicity of these poisonous particles.
The researchers from the Centre for Misfolding Diseases in the Chemistry Department at Cambridge University and Georgetown University and the National Institutes of Health in the US, tested squalamine in both cell cultures in the lab, and in an animal model using nematode worms. 

Progress

While their findings only represent a step towards a treatment for Parkinson’s Disease in humans, they described the results as representing “significant progress”.
Professor Christopher Dobson, study author, Master of St John’s College and a professor in the university’s chemistry department, 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.
Professor Christopher Dobson, study author, said the results were promising
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.”
Professor Michele Vendruscolo, from the Department of Chemistry and a co-author, said: “This is an encouraging step forward in our efforts to discover potential drugs against Parkinson’s Disease.
“Squalamine can prevent alpha-synuclein from malfunctioning, essentially by normalising its binding to lipid membranes. 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 – 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.

Implications

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 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 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.
They then 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.

Research

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.
Scientists say further research is 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.
“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.”
http://www.cambridge-news.co.uk/news/health/cambridge-scientists-make-revolutionary-discovery-12463603

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