A naturally occurring steroid found in the dogfish shark may be the key to treating Parkinson’s disease, according to findings published in the Proceedings of the National Academy of Sciences.

In Parkinson’s disease, alpha-synuclein (α-synuclein), a normal protein present within the nervous system, forms clumps that damage and ultimately destroy the neurons where they form.

In a pre-clinical model, scientists discovered that a synthesized version of squalamine, a steroid found in the dogfish shark (made in a process that does not involve use of any natural shark tissue) could prevent the buildup of these α-synuclein clumps, and potentially reduce the clumps that already existed. This breakthrough has significant therapeutic potential for patients with Parkinson’s disease, said the study’s co-senior author, Michael Zasloff, M.D. Ph.D, professor of surgery and pediatrics at Georgetown University School of Medicine and scientific director of the MedStar Georgetown Transplant Institute, in an exclusive interview with R&D Magazine.

“This has the potential, assuming it proves to be safe, to slow down or stop the continued formation of α-synuclein aggregates,” said Zasloff, who discovered squalamine in the dogfish shark in 1993 and synthesized it in 1995. “The hope is by blocking the aggregate process, continued damage to the nervous system could be prevented. If the individual had sufficient capacity for regeneration, certain types of recovery could also occur. In areas of the brain and the nervous system where the presence of aggregates impaired function but didn’t destroy those nerves, these functionalities could be restored with squalamine.”

The study utilized an animal model of worms that had been genetically engineered to produce human α-synuclein in their muscles. As the worms continued to grow and accumulate α-synuclein, those not treated with squalamine experienced buildups that begin to damage their functional activity. This eventually leads to paralysis, said Zasloff. Those that were treated with squalamine saw a different result.

“If these worms are given squalamine, there is inhibition of the aggregates and complete rescue of the animals from paralysis,” he said. “These results were very surprising.”

How it works

The mechanism of action of synuclein—which Zasloff has been studying for more than 20 years— is well understood. 

Squalamine is a positively charged molecule with a high affinity for negatively charged membranes, explained Zasloff. When it enters a cell, it fits on a particularly negatively charged membrane inside that cell, and kicks off proteins that are stuck on.

“It turns out that α-synuclein, a protein made in many different cells, sticks to the same sort of membranes that squalamine happens to love to go to,” said Zasloff. “As a consequence of that, it seemed reasonable to explore whether or not squalamine would actually be capable of first preventing α-synuclein from sticking to a membrane, but also more importantly, prevent α-synuclein from aggregating.”

The pre-clinical model showed that squalamine, in worms, could prevent and eliminates α-synuclein build up inside neurons by unsticking the protein from the inner wall of nerve cells. It could also protect healthy human neuronal cells from being damaged by exposure to pre-formed toxic masses of α-synuclein, by preventing them from adhering to the outer membrane of the neuronal cells.

Based on these findings, a multi-center clinical trial in human patients with Parkinson’s disease is planned for 2017, said Zasloff. In this trial, squalamine will be given orally to patients with the disease. The focus will be on treating from the gut out, he said.

“There is a great deal of research right now in Parkinson’s that argues, and I am big believer in this, that the problem in Parkinson’s begins in the gut,” said Zasloff. “The hypothesis on this is that aggregates form and α-synuclein is produced in great amounts in the nervous system of the gut. Once it’s made in the neurons of the gut, it travels up the nerves that connect the gut’s nervous system to the brain, and then finds its way into the brain stem and begins to travel throughout the brain. Our belief is that by preventing aggregation within the nervous system of the gut, we could ultimately impact on events that are taking place throughout the brain.”

If this approach is successful in Parkinson’s patients, squalamine may be investigated in other similar diseases as well.