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Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) all affect the brain. They can cause problems ranging from dementia through to paralysis.
“The RobustSynapses project addressed one of the largest unmet medical needs – the fact that there are no cures for any of these major neurodegenerative conditions,” explains RobustSynapses principal investigator Patrik Verstreken, scientific director and group leader at the VIB Center for Brain & Disease Research at KU Leuven, Belgium. “To meet this challenge, we wanted to zoom in on what is happening at the earliest stages of these diseases.”
More effective treatments
More specifically, the EU-funded RobustSynapses project focused on synapses. These small connections, which exist between nerve cell endings in the brain, enable signals to pass from one neuron to the next. Synapses are therefore critical to the brain’s function. They are also often the first site to be affected during neurodegenerative disease progression.
In this European Research Council-supported project, Verstreken wanted to achieve a better understanding of how exactly these synapses function, and what might make things go wrong. His hypothesis was that this knowledge could enable medical professionals to one day identify disease progression earlier, and to be able to intervene more effectively. This could lead to more effective treatments, and the alleviation of problems for patients later.
The project team began by studying what was happening at synapses in fruit flies, applying novel genome-editing methods. “What we found from this was that there are specific mechanisms at the synapse that are needed to remove dysfunctional debris,” adds Verstreken. “If this doesn’t happen, the synapses fail, causing problems.”
Next, the team applied these findings in vitro to human neurons, generated from the skin cells of patients. This combination of approaches enabled the project team to first study synaptic processes live, and to then confirm – or not – their discoveries in human nerve cells.
A critical finding, confirmed by both these approaches, was that problems at the synapse were being caused by a process called ‘Synapse-specific autophagy’. This discovery, Verstreken believes, could create new opportunities for therapeutic targets in the treatment of neurological disorders. “One of our most exciting innovations was that we were able to develop tools that interfere with the defects induced by this process at synaptic contacts, including cognitive decline,” he says. “We are now pursuing this in the hope of developing real therapeutic interventions.”
Exciting research opportunities
This work is continuing apace in Verstreken’s lab. “First, we are using single cell approaches to define which cells in the brain are most affected by the synaptic processes we uncovered,” he explains. “One exciting discovery has been finding out why Parkinson’s disease patients suffer from sleep problems.”
Verstreken plans to expand this particular line of research in the future, searching for additional affected cells in the brains of patients. These can then be modelled in appropriate systems in the lab, either, as in this project, in live animals, or in human neurons derived from skin cells.
“Second, as I discussed earlier, we found a way to interfere with the effects of ‘synaptic autophagy’,” Verstreken continues. “We can achieve this by manipulating proteins that are central to the process and that are also found to cause risk to Parkinson’s disease when mutated in patients. We are now developing effective tools to achieve this, together with our industry partners.”
The exciting research opportunities generated by the RobustSynapses project has opened the door to new approaches to neurodegenerative diseases. Given that there are no cures at present, identifying possible new avenues for new therapeutics could have a hugely positive effect on humanity. “Given the large number of people suffering from neurodegeneration, the impact could be very sizeable,” concludes Verstreken.