Shark-derived compound could help fight Parkinson's
In the 1990s, US researchers discovered the secret to the dogfish shark's hardy immune system – squalamine, a potent antiviral and antibiotic compound that could protect liver and blood tissues from viral infections. Synthetic versions of the compound have since been produced and used in cancer clinical trials without any major side effects. Now, a new study has found there's a good chance it could also be used to treat the symptoms of Parkinson's disease.
Key to the findings of this new study is the effect of squalamine on the protein alpha-synuclein, which can clump together to form toxic plaques known as Lewy Bodies, one of the hallmarks of the disease. Previous animal studies by co-author Michael Zasloff, a professor of surgery and pediatrics at Georgetown University (who was incidentally also the lead researcher of the team that discovered squalamine in 1993), showed how squalamine prevented viruses from replicating by disrupting membrane interactions, a key process.
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In this new study, the researchers wanted to find out if squalamine could displace alpha-synuclein from cell membranes. This is significant because alpha-synuclein works by binding to the membranes of tiny structures called synaptic vesicles, which help to transfer neurotransmitters between neurons. Normally, the protein helps promote the flow of chemical signals, but trouble occurs when it breaks down and starts clumping together, creating the dreaded toxic clusters that are the calling card of Parkinson's disease.
In their experiments, squalamine did indeed prevent clusters of the protein from forming by competing for binding sites on the surfaces of the vesicles, thus significantly reducing the rate at which the toxic particles could form. Not only that, tests conducted on human neuronal cells also demonstrated that the compound was able to reduce the toxicity of these particles.
"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," says Christopher Dobson, a co-author and professor of chemistry at the University of Cambridge. "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."
"If there are going to be ways to beat the disease, it seems likely that this is one that may work," adds his departmental colleague and co-author Michele Vendruscolo.
A promising lead
In addition, worms that were genetically programmed to over-express alpha-synuclein in their muscle cells and should have been paralyzed by the clumping compound, turned out to be just fine. "We could literally see that the oral treatment of squalamine did not allow alpha-synuclein to cluster, and prevented muscular paralysis inside the worms," says Zasloff, who is now planning a US clinical trial involving Parkinson's disease patients.
Frequently, Parkinson's patients are beset by severe constipation and Zasloff says squalamine might help with that as well. Vendruscolo also suggests there is a possibility that targeting areas such as the gut could also delay the onset of the disease by sending signals to other parts of the body.
"Targeting alpha-synuclein in the gut may perhaps in some cases be sufficient to delay the progress of other aspects of Parkinson's disease, at least for symptoms concerning the peripheral nervous system," he says.
That being said, as promising as the results might be, further research is needed to determine how squalamine can be developed to benefit human subjects and what form such a drug would take. The question of how researchers should go about administering the drug to the specific neural regions where the disease first takes root also remains.
"In many ways squalamine gives us a lead rather than a definitive treatment," says Dobson. "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 study was published in Proceedings of the National Academy of Sciences.