Searching for the mechanism behind the most common genetic form of Parkinson’s disease. Researcher in the Spotlight: Prof. Wim Vandenberghe

“We are studying a newly discovered gene that could help us understand what goes wrong in the brain in Parkinson’s disease. If we can understand that, we can look more specifically for a drug that could slow the disease down.” Prof. Wim Vandenberghe, UZ Leuven / KU Leuven

Prof. Wim Vandenberghe is a neurologist at UZ Leuven and a professor at KU Leuven. He combines the care of people with Parkinson’s and Huntington’s disease with laboratory research into the molecular causes of Parkinson’s disease, with a particular focus on the LRRK2 and RAB32 genes. In 2026, the Demoucelle Parkinson Charity provided seed funding for the research project described below:

—–

Why are you both a neurologist and a researcher?

“I wouldn’t like to be just one or the other. If I only saw patients, I would mainly notice how much we still cannot solve: we still cannot slow the disease down. I often follow people with Parkinson’s disease for many years, and it is frustrating to see them deteriorate without being able to do much about it. That is a major motivation for me to do research.

But I also don’t think my research would progress faster if I were only a researcher. Because I see patients, I have a better understanding of what our research should focus on. And because patients trust me, they are also more willing to take part in research. For example, by donating a small piece of skin from which we can grow nerve cells in the laboratory.”

As a researcher, you work extensively on a gene called LRRK2. What exactly is it, and why is it so important?

“Almost thirty years ago, scientists discovered the very first gene that can cause Parkinson’s disease when it contains a mutation. That was a major breakthrough. Before that, no cause of Parkinson’s disease had been proven. Since then, a number of other Parkinson’s genes have been discovered. LRRK2 is the gene in which mutations that cause Parkinson’s disease occur most frequently.

But we still do not fully understand what LRRK2 actually does, because LRRK2 is unfortunately a very complicated protein. LRRK2 is thought to be involved in controlling the transport of membranes within cells. Membranes are thin layers that can enclose cellular components. When there is a mutation in LRRK2, LRRK2 becomes overactive. That is why scientists are now trying to develop drugs that inhibit LRRK2. This is proving difficult: a first major clinical trial with such a drug unfortunately did not produce a positive result. A new study, specifically involving people with an LRRK2 mutation, is still ongoing.”

Precisely because LRRK2 is proving to be such a difficult target, you are also looking at another avenue. What does your own research focus on?

“We are studying RAB32, a newly discovered gene that is also linked to Parkinson’s disease. It has been almost fifteen years since another new Parkinson’s gene was discovered. RAB32 and LRRK2 can bind to each other, which suggests that they work together and influence one another. There are even indications that a mutation in RAB32 may cause LRRK2 to become even more active. If that is correct, it might be possible to inhibit LRRK2 by targeting RAB32.

What particularly interests us is that RAB32 may act more specifically than LRRK2. LRRK2 has all kinds of effects, which can also differ between cell types. LRRK2 is found not only in brain cells, but also in your lungs, kidneys and immune system. A drug that inhibits LRRK2 could therefore also have effects on these other organs and potentially cause side effects. We hope that RAB32 acts more specifically, which could make it a safer target for treatment. But we still do not know exactly what RAB32 does or precisely how it works together with LRRK2.

To investigate this, we grow nerve cells in the laboratory from stem cells. Stem cells are primitive cells that can still develop into almost any type of cell in the body. These stem cells are derived from skin cells from people with Parkinson’s disease and from healthy people. Each time, we compare two cell lines with exactly the same DNA, apart from one difference: that specific mutation in RAB32. This allows us to be sure that any difference we observe is genuinely caused by that mutation.”

Why do you work with stem cells?

“With cancer, researchers can simply remove diseased cells from a patient, for example through surgery, a biopsy or a blood sample. With Parkinson’s disease, that is not possible: the diseased nerve cells are located deep inside the brain, and we can only study them after someone has died. By then, the most vulnerable cells have often disappeared long ago, and so much damage has already occurred that it is difficult to see what went wrong at the beginning of the disease.

Stem cells make this possible. We grow nerve cells from a person with Parkinson’s disease in the laboratory, and after about two months we can already look at the very first things that go wrong, long before the cell itself becomes truly diseased. Using cells with an LRRK2 mutation, we have already observed subtle early differences in this way, even though the cells themselves still appeared perfectly healthy at first glance. We will also look for the first processes that go wrong in nerve cells with a RAB32 mutation. Among other things, we are looking at the processes by which nerve cells clear away their waste, because disruption of these waste-clearance processes also repeatedly emerges in other genetic forms of Parkinson’s disease.

And that is ultimately what it is all about. If we understand how a mutation in RAB32 causes Parkinson’s disease, we will also have new targets that could be addressed with new drugs: not only RAB32 itself, but also other proteins involved in the same process. The more potential targets we identify, the greater the chance that we will find one that can lead to a real treatment.

This knowledge could also help us understand Parkinson’s disease in people who do not have a known genetic mutation. Doctors see very little difference in symptoms between Parkinson’s disease caused by an LRRK2 or RAB32 mutation and the more common form of the disease. This suggests that similar processes may also go wrong in Parkinson’s disease without these genetic mutations.”