Targeting a troublesome protein in Parkinson’s

To be able to develop treatments that will slow, stop or reverse Parkinson’s, we need to understand what’s going on in brain cells to cause them to become damaged and die.

As the largest European funder of Parkinson’s research, we’ve been supporting researchers to identify these causes, and translate them into future treatments. 

Proteins perform most of the jobs in our cells. But to function properly, proteins have to be the correct shape and this depends on them folding properly. 

In the early 1900s, scientists looking at brain tissue from people who had lived with Parkinson’s under the microscope noticed large clumps present in the cells. In 1997, further research showed that these clumps were made up of a protein called alpha-synuclein, which wasn’t folding properly.

Protein misfolding is common in many brain conditions that get worse over time, including Alzheimer’s and Huntington’s. Misfolded proteins are problematic because they put extra strain on the cell’s recycling system, which works to remove unwanted materials from the cell. They can also start to form protein clumps. These clumps, also known as protein aggregates, can quickly become toxic to cells, making it harder and harder for them to work properly, and eventually causing cell death.

This seems to be what’s happening in Parkinson’s with alpha-synuclein. The sticky proteins form clumps which may play a crucial part in the death of vital brain cells. This makes alpha-synuclein a good target to find treatments that slow down Parkinson’s.

Over the past 30 years, our funding has been critical for piecing together how alpha-synuclein is involved in the onset of Parkinson’s. All of this crucial research has helped us get to a point where we’re seeing treatments in the final stages of testing that have the potential to slow down the progression of Parkinson’s. Take a look at some of the research that’s paved the way for today’s drug trials:

How does alpha-synuclein stick together?

Parkinson’s UK-funded researcher Professor Maria Grazia Spillantini has been a driving force behind much of the alpha-synuclein research to date. In 2006, we funded her work that found that smaller, misfolded forms of alpha-synuclein clump together more easily. Her team also found that it was harder to break the clumps down into waste products and remove them from the nerve cells in the brain, where they kept building up.

Not only did the clumps affect parts of the brain that produce dopamine, but also other areas which are associated with motor control, decision making , emotions and smell. This could help explain some of the non-motor symptoms that are associated with Parkinson’s.

Stopping the spread of alpha-synuclein

Research has suggested that alpha-synuclein may also spread from cell to cell inside the brain. We funded researchers in London and Oxford who showed that toxic, misfolded alpha-synuclein can escape from brain cells and be taken into neighbouring cells, which then go on to develop problems.

This seems to happen when the cell’s waste recycling centre is not working correctly, leading to a build-up of abnormal alpha-synuclein clumps which eventually escape from the cell. 

Does Parkinson's start in the gut?

The brain isn’t the only place where the spread of toxic alpha-synuclein may be happening. Recent research has also found misfolded alpha-synuclein in the gut of those in the early stages of Parkinson's. Now we’re funding Professor Spillantini to study mice which produce alpha-synuclein in the gut, to see if and how this alpha-synuclein makes its way to the brain.

If we can confirm that alpha-synuclein clumps form in the gut before travelling to the brain, we can look at the gut as a potential way to diagnose and treat Parkinson’s earlier.

Now we have more of an understanding of what alpha-synuclein does, it’s become a very promising candidate for drugs that might be able to slow, or stop Parkinson’s getting worse over time.

There are currently 3 treatments in phase 3 of testing that target alpha-synuclein in different ways. All 3 are being investigated for their potential to slow or stop progression of Parkinson’s. Read more about the phases of clinical trials in our research glossary.

A vaccine for Parkinson’s?

One promising drug candidate is being led by pharmaceutical company Roche. They’re developing an antibody, called prasinezumab, that binds specifically to clumps of alpha-synuclein, working in a similar way to a vaccine. The antibody will try to break the protein clumps down, and prevent them from spreading. It’s given as an infusion into the arm via a drip.

An early trial was carried out with 80 people. Results were published in June 2018 and showed  that the treatment was safe and there was reduced alpha-synuclein in the blood. This is good because this will lead to less protein being able to form sticky clumps.

In 2024, a larger trial of the drug didn’t show a significant benefit for people when compared to those on a placebo (dummy) drug within the timeframe of the trial. But participants said that they felt better on the drug, and other tests showed there could be possible benefits that weren’t captured in the study.

So in 2026 they launched a longer, phase 3 study of the drug. Participants will take either prasinezumab or a placebo for up to 3 years. Find out more about the trial on our Take Part Hub.

Clearing out alpha-synuclein clumps

Another potential drug in phase 3 of testing is ambroxol. This is a repurposed drug, and is currently a component of a cough medicine. It works by boosting an enzyme in the cell which is involved in waste recycling, and therefore clearing away excess alpha-synuclein waste.

In 2023 we announced we’d joined forces with Cure Parkinson’s to co-fund a phase 3 study, recruiting 330 people to see if ambroxol can slow down Parkinson’s symptoms getting worse. The study is currently ongoing.

Read more about the ambroxol trial.

Stopping alpha-synuclein production

Finally, pharmaceutical company Annovis Bio is testing a new drug called buntanetap. The drug is designed to stop overproduction of alpha-synuclein n cells. It does this by preventing the instructions for creating alpha-synuclein from being used. This should reduce the number of clumps that are formed.

Early studies of buntanetap looked very promising, with participants on the trial showing fewer changes to their symptoms while those on placebo got worse over time. This was particularly seen in thinking and memory changes between the groups. 

The company is now working on a much longer study of buntanetap, which is currently running across sites in the United States. They’ll also be asking people who have had deep brain stimulation surgery to take part in the trial, to see if there’s also a benefit for people who have had this procedure. The trial is recruiting now and will run for 3 years.