Sharks, Parkinson’s and dementia: what’s the link?

Why are fish so good at fighting off infection? It’s the question that just might have started the ball rolling on a new drug treatment for Parkinson’s-related dementia.

In 1993, Dr Michael Zasloff, discovered the answer to this fishy conundrum in the liver of dogfish sharks: a naturally occurring steroid which the team of researchers named squalamine. Find out more about the research into squalamine on the PNAS website.

Squalamine has anti-microbial properties against both bacteria and viruses. It has shown promise in clinical trials for cancer but perhaps its most interesting ability relates to its interaction with problematic proteins alpha-synuclein, beta-amyloid, tau and TDP-43.

The problem with tangled up proteins

When it comes to neurodegenerative conditions, there seems to be a common issue: proteins that become tangled up inside nerve cells and become toxic.

• In Parkinson’s, the culprit is alpha-synuclein.
• In Alzheimer’s, both tau and beta-amyloid get tangled up.
• Tau also plays a role in progressive supranuclear palsy.
• The protein TDP-43 has been seen to accumulate in motor neurone disease and certain types of dementia.
• And in Huntington’s, the protein huntingtin builds up in clumps.

While there is still much we don’t know about how and why they form, there is a general consensus that these clumps, tangles, plaques and aggregates can be damaging and are likely at the route of all these conditions. There is also much we don’t know about the proteins involved in forming these clumps, but researchers are uncovering more about the role they play. For instance, it is now believed that alpha-synuclein can be produced by nerve cells in the gut in response to infection, and protects us by calling on the immune system to help defend us.

Perhaps the complexity of the problem with protein tangles underscores why we lack treatments that slow the progression of all these conditions. But there is also hope that identifying drugs that slow or stop the proteins from becoming tangled and toxic could be key to halting progression.

It’s not just alpha-synuclein that Parkinson’s researchers have their eye on. The Alzheimer’s proteins, beta-amyloid and tau, also seem to be involved in the onset and progression of Parkinson’s-related dementia.

It is understandable, then, that the discovery that squalamine and other related chemicals called aminosterols can reduce alpha-synuclein and amyloid-beta from forming clumps might be of interest in the fight against dementia.

From nature to medication

The first step in turning a natural compound into a potential drug is making enough of it. Much like levodopa, which is a naturally occurring molecule but can be man-made to create medications for Parkinson’s, researchers have also worked out how to make synthetic squalamine and other aminosterols with toxic protein-busting properties. And in the process of making and testing different types of aminosterol in the lab, they have found that different molecules may be better at fighting off the protein clumps that form in different neurodegenerative conditions.

The next step is making sure your potential drug molecule can get to where it is needed. When we talk about treatments for Parkinson’s, this often means a drug needs to get into the brain. Some aminosterols have a natural ability to pass through the protective barrier that surrounds the brain, known as the blood-brain barrier. But others do not have this ability.

Fortunately, in the case of squalamine, the researchers are interested in the effects this molecule can have outside the brain, specifically in the gut. This means that a drug based on this molecule doesn’t need to get into the brain, and doesn’t even get absorbed into the bloodstream.

The road to Parkinson’s-related dementia

It is in the clinical trial stages where we pick up the story of the aminosterol ENT-01, a synthetic version of squalamine that has been developed by the US-based biotech company Enterin Inc.

ENT-01 hasn’t started life as a dementia drug, instead previous clinical trials have shown it has potential for targeting alpha-synuclein clumps outside the brain.

One of the theories on where Parkinson’s may start, at least in some people with the condition, involves the gut. Clumps of alpha-synuclein have been found in the gut before Parkinson’s symptoms have developed, leading researchers to believe it is in the nerve cells of the gut where the protein first accumulates. From here the alpha-synuclein can travel up the vagus nerve which directly connects the gut to the brain.

Early clinical trials of ENT-01 demonstrated the drug was safe and showed potential for reducing constipation in people with Parkinson’s, but they also pointed towards additional benefits including possible improvements in depression, cognition, hallucinations, and sleep problems in placebo-controlled trials. The positive effect on the brain is believed to be because of squalamine’s impact on the vagus nerve that relays messages from the gut to the brain.

Read more about the early clinical trials of ENT-01 on the Parkinson's News Today website.

ENT-01 for Parkinson’s-related dementia

In 2022, a placebo-controlled phase 2b trial of ENT-01 to test the safety and efficacy of the drug in people with Parkinson’s was completed. The study showed significant improvement in constipation, and signalled benefit in psychosis and dementia.

Today, with this phase 2b trial being completed, Enterin Inc. is planning the next stage of clinical trials to confirm the potential anti-dementia activity of ENT-01 and with investment from the Parkinson’s Virtual Biotech, plan to launch a placebo-controlled phase 2b in the UK and US next year.

Dr Arthur Roach, Director of Research at Parkinson's UK, said:

From shark liver to Parkinson’s trial

We’re far from the end of the story with squalamine. The trial is not yet looking for participants but we will keep our networks up to date. To find out about opportunities to take part in research, visit our Take Part Hub for studies that are recruiting right now or sign up to our Research Support Network and get information about new opportunities as they open.