The Synapse Series - How Patrik Verstreken’s basic research advances multiple fields

26 February 2017
​Patrik Verstreken (VIB-KU Leuven) specializes in brain research, with a particular focus on synapses. In various brain disorders, these junctions between nerve cells play a pivotal role. With an impressive series of leading papers published in the past few months, Patrik illustrates how focused and continued basic research can lead to breakthroughs applicable to a wide range of neurological diseases, including epilepsy, Parkinson’s disease and Alzheimer’s disease.
 
It is well-known that brain cells ‘talk’ to one another through synapses. But while considerable progress has been made in identifying the proteins present at the synapse, the roles of many of them in controlling synaptic functions remain poorly defined. That’s why Patrik has made it his business to fully understand what happens at these crucial brain junctions.
 
Patrik, why are you specifically interested in synapses?
“Synapses are really the ‘business end’ of the brain. They transmit electrical signals from one brain cell to the next, and in doing so, they adapt and modulate the signals. The formation and breakdown of these contacts and the way they function are of critical importance to the way our brains ‘see’ and store information, like memories.
 
The intriguing thing is that neurons are extremely polarized. Synapses are often very far away from the cell body, where DNA is stored and proteins are generated. Dopaminergic neurons, for example, are over 5.5 meters long! In order to bridge this distance, synapses need to operate independently for a large part. This is what we are studying in the lab: how do synapses regulate their own business independently? How do they maintain their function and how does this go astray in disease?”
 
Your work clearly shows the importance of basic research. Does it always come first for you?
“Yes, all our work is ‘basic’ in nature, even when we study genes related to disease. I am convinced that the only way to fundamentally understand a disease is to delineate the pathways affected and the mechanisms by which the relevant proteins, lipids and organelles operate. Taking shortcuts isn’t going to work and it is critically important that we continuously remind funding bodies of that fact.
 
We haven’t seen any major new medications for neurodegenerative conditions in the last 30 years or so. This is because we do not sufficiently understand the mechanisms behind these diseases. It is well-accepted that conditions such as Alzheimer’s and Parkinson’s disease originate at the synapse. However, we do not completely understand how synapses maintain their functions throughout the life of an organism. We need to understand how these diseases are affecting the synaptic machinery.”
 
Do you have any advice for young researchers when it comes to pursuing basic science?
“Sure. Follow your interests, explore the world and above all, believe in yourself. This will help you in spotting opportunities. Most exciting discoveries are unplanned, so it’s important to explore broadly. However, once you spot an opportunity, you have to bring focus to your ideas and your work.” 
 
You have collaborated with a variety of research partners. How do you find the right ones?
“It goes both ways. We seek out collaborators to help us with aspects of our work, while others come to us with their questions. There are multiple ways these collaborations see the light: from informal and general contacts at meetings to direct inquiries about a certain expertise. I believe that the key ingredients for a prosperous long term collaboration are trust and openness. So far, I haven’t had any bad experiences with collaborations. I’m convinced that, as science becomes more and more multidisciplinary, it is crucial to find the right partners to drive our research lines forward.”
 
In the past months, you have published new findings at a remarkable pace. How did you manage this?
“Strategic collaborations, significant investments in technology and the generation of transgenic animals all help us speed up our ability to conduct experiments. That said, our recent publications are the result of projects that have been running for many years, thanks to the efforts of numerous people.  Our collaboration with the Versées lab in Brussels, for example, has been ongoing for over five years and has three lead authors.” 
 
 
“Most exciting discoveries are unplanned, so it’s important to explore broadly.”
 
How difficult is it to set priorities and decide where to put your research focus?
“There is a lot of serendipity in research and I’ve come to trust my gut feelings when it comes to pursuing specific research lines or not. Our first aim is always to isolate processes that are critical for synaptic function.  They are unvaryingly connected to neuronal disease, and in many cases, Parkinson’s disease specifically. For me, this is the time to formulate an exciting hypothesis and test it. Our initial ideas are almost never correct, and as the data comes in, we adapt our model and formulate new hypotheses.”
 
How do you see the future of your research field? Are we on the brink of some major breakthroughs?
“I do believe there are great breakthroughs on the horizon as we start to understand more and more about synaptic function – and dysfunction. However, this acceleration will only happen by pushing for more mechanistic basic research. This type of research yields new and unexpected targets for disease, as we and other VIB research groups have shown many times.  Efficient translation of these discoveries by bringing more targets to the level of clinical tests will then smooth the path toward curing these diseases. Hence, I believe we need to invest in both, but we surely shouldn’t forget where it all starts. Basic research will always be crucial to understanding and curing neurodegenerative and neuronal disease.”
  
  
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September 2016: possible new treatment for epilepsy
(Fischer et al., Nature Structural & Molecular Biology 2016)
 
Research carried out in collaboration with professor Wim Versées (VIB-Vrije Universiteit Brussel) came to a surprising conclusion: increasing the concentration of specific fats in the brain is a possible strategy for preventing epileptic seizures.
 
October 2016: disruption at the root of Parkinson’s disease uncovered
(Soukup et al., Neuron 2016)
 
Research from the group of Patrik has shown for the first time that a malfunctioning stress-coping mechanism in the brain is at the root of Parkinson’s disease. Genetic mutations that cause Parkinson’s disease can prevent synapses from coping with the stress of intense brain activity. This damages the synapses and disrupts the transmission of brain signals.
 
Synapses transmit an enormous amount of electrical signals. Some neurons will fire more than 800 times in just one second. Patrik’s team discovered that synaptic contacts have developed special mechanisms to deal with such a ‘barrage’ of signals. However, if one of these mechanisms doesn’t function properly, cellular stress is accumulated. This causes damage and ultimately leads to neurodegeneration.
 
Patrik’s team investigated different types of coping mechanisms and uncovered that one type is disrupted in Parkinson’s disease. This aberration involves different known genetic factors and affects synapses specifically. Building on these findings, the team hopes to correct the dysfunction and find strategies to re-establish normal synaptic communication.
 
November 2016: insights into how Alzheimer’s spreads through the brain
(Calafate et al., Cell Reports 2016)
 
Synapses play a pivotal role in the transmission of toxic proteins. This allows neurodegenerative diseases such as Alzheimer’s to spread through the brain. This was the main conclusion of research by Sara Calafate and Patrik, in collaboration with Janssen Pharmaceutical Companies (Johnson & Johnson).
 
During the courses of neurodegenerative diseases including Alzheimer’s, toxic proteins are known to spread throughout the brain. As the disease progresses, more and more brain areas are affected. It was well-understood that the disease follows existing brain pathways, but so far it wasn’t clear which processes enabled the spread itself.
 
The researchers offered proof that synapses are critical to mediating the transmission of toxic protein species, and reveal the mechanisms behind this process. They show that the toxic proteins cross from one brain cell to the next by being engulfed by ‘vesicles’, small particles in brain fluid. Once they are in the receiving cell, the vesicles burst and release the toxic proteins. If the spreading of these toxic proteins could be prevented, the progression of neurodegenerative diseases might be slowed down substantially.
 


​Patrik Verstreken (VIB-KU Leuven) ​
©VIB-Ine Dehandschutte