Breakthrough Prize 2024

...how large was your search area?

We narrowed it down to a few million base pairs. And this sheer number explains why it took until 2004 for us to make a find.

That discovery is already 20 years ago now, but then as today, Parkinson's is incurable. What has happened behind the scenes during this time?

Most researchers in this field are of the opinion that the way to a treatment is to know the different gene variants that lead to hereditary forms of Parkinson's. And we know much more about them today than we did in 2004. We are confident that one day we will be able to get to the roots of Parkinson's - and that the onset of the disease can be at least postponed or even prevented altogether.

Wait: You are now explicitly talking about the hereditary forms of Parkinson's disease. But most patients have the sporadic form, i.e. without a hereditary predisposition.

That is the real point: the mechanisms are very likely the same. Approaches that have their foundation somewhere in the genes are much more likely to succeed than anything that has been tried without knowledge of this genetic component.

You were part of the discovery of yet another of these mutations in another gene: the GBA mutation. For simplicity, one usually speaks of the GBA mutation.

And there, too, we are much further along today than we were 20 years ago. We now know: Patients with the GBA mutation usually develop a particularly severe form of Parkinson's disease. In addition to the classic motor impairments, they also develop dementia.

It is precisely these patients who are the target of a clinical trial that you are about to start. What is it all about?

With this study, we want to work around a typical problem that we often face when testing therapies for neurodegenerative diseases: In those patients who already show symptoms, the disease is so advanced that we come too late. But of course we can only start therapy when a patient has symptoms. With the GBA study, we break this vicious circle because dementia does not develop until later in the course of the disease. This means that when the first typical Parkinson's symptoms appear in a patient who has the GBA mutation - for example, motor impairments - we can treat the dementia pre-symptomatically at that moment, because it only develops later.

If your therapy is effective, does it work for all dementia patients?

No, it specifically targets Parkinson's dementia in GBA patients. But we have another hope: since a few years now, it is possible to detect the formation of so-called alpha-synuclein deposits through the cerebrospinal fluid. These are deposits of proteins that mainly occur in all PD patients, but cause dementia in those with GBA mutations - and we attack these deposits with our therapy. To do this, we administer special antibodies.

The study will involve 120 individuals in several countries with specific GBA mutations. Are your two American colleagues Ellen Sidransky and Andrew Singleton, who together with you received the Breakthrough Prize for the discovery of risk genes, also involved?

No, the planned GBA study is purely European. In regulatory terms, this is difficult enough! But of course I am still in contact with Ellen and Andy. There are very strong international networks in Parkinson's genetics research, because everyone knows how promising close cooperation is. Together, we were among the co-founders of the IPDGC - the International Parkinson Disease Genetics Consortium. At that time, we were six or eight researchers from different countries.

Is there any evidence that genetic differences are significant when it comes to Parkinson's?

Absolutely! I'll give you a very recent example: a new variant of the GBA gene has now been found that was previously unknown. It occurs specifically in the population of Sub-Saharan Africa.

DZNE is traditionally strongly positioned in such international collaborations. What do you think is the unique selling point of DZNE?

We are very strong in the area of basic molecular research. And I'm not just talking about Parkinson's, but also, for example, about colleagues working on Alzheimer's or rare neurodegenerative diseases such as ataxias. And we are also strong in clinical research due to our nationwide network and close collaboration with university hospitals.

The Breakthrough Prize, with which you were awarded, is the world's largest science prize. What can actually come next in your research?

(laughs) My motivation is still very high, if that's what you mean. My big goal is related to the GBA study we talked about: We want to show for the first time that genetic stratification of patients can lead to effective therapy. I am still burning for research!

^{Interview: Kilian Kirchgeßner}