Summary: Researchers have discovered a genetic mutation that causes Parkinson’s can prevent synapses from coping with the stress of intense brain activity.
Source: VIB Flanders.
Leading-edge research by the team of professor Patrik Verstreken (VIB-KU Leuven) 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 – the junctions between neurons where electrical signals are transmitted – from coping with the stress of intense brain activity. This damages the synapses, which in turn disrupts the transmission of brain signals. Building on these findings, the scientists hope to correct the dysfunction and find strategies to re-establish normal synaptic communication. The results are published in the leading trade journal Neuron.
Professor Patrik Verstreken (VIB-KU Leuven) specializes in brain research, with a particular interest in synapses, the place where neurons contact one another and transmit signals. In various brain disorders – like Parkinson’s disease – communication at these synapses is impaired. The new research identifies an important cause of this disruption.
Patrik Verstreken (VIB-KU Leuven): “Synapses have to transmit an enormous amount of electrical signals. Some neurons will fire more than 800 of those signals in just one second. We have 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 to the synapses and ultimately leads to neurodegeneration.”
Maintaining synaptic function
Professor Verstreken’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 specifically synapses.
Patrik Verstreken (VIB-KU Leuven): “Our work is the first to implicate dysfunctional synapses so profoundly in Parkinson’s. After using mostly fruit flies to understand the disease mechanism it will now be interesting to see whether an identical stress-coping mechanism is disrupted in human patients as well. Our collaborators at the European Neuroscience Institute in Göttingen led by Ira Milosevic already made very similar discoveries in mouse neurons. In any case, this research tells us that it is absolutely critical to find strategies to maintain synaptic function in treating this disease.”
Building on the results of this research, the scientists want to find out how universal the stress-coping mechanism is disrupted in Parkinson’s disease.
Patrik Verstreken (VIB-KU Leuven): “Next, we hope to correct the dysfunction caused by the Parkinson mutations and identify strategies that might re-establish normal synaptic communication. Reactivation of the coping mechanism, for instance, might also repair the damaged synapses. Of course, this requires additional research.”
Source: VIB Flanders
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Original Research: Abstract for “A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals” by Sandra-Fausia Soukup, Sabine Kuenen, Roeland Vanhauwaert, Julia Manetsberger, Sergio Hernández-Díaz, Jef Swerts, Nils Schoovaerts, Sven Vilain, Natalia V. Gounko, Katlijn Vints, Ann Geens, Bart De Strooper, and Patrik Verstreken in Neuron. Published online September 15 2016 doi:10.1016/j.neuron.2016.09.037
A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals
•Autophagosomes at synapses have a distinct morphology
•EndophilinA acts in endocytosis but also in autophagy at synapses to recruit Atg3
•EndoA S75 phosphorylation by the Parkinson’s disease kinase LRRK2 promotes autophagy
•Imbalances in EndoA phosphorylation cause dopaminergic neuron degeneration
Synapses are often far from the soma and independently cope with proteopathic stress induced by intense neuronal activity. However, how presynaptic compartments turn over proteins is poorly understood. We show that the synapse-enriched protein EndophilinA, thus far studied for its role in endocytosis, induces macroautophagy at presynaptic terminals. We find that EndophilinA executes this unexpected function at least partly independent of its role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is blocked in animals where EndophilinA cannot be phosphorylated. EndophilinA-phosphorylation promotes the formation of highly curved membranes, and reconstitution experiments show these curved membranes serve as docking stations for autophagic factors, including Atg3. Functionally, deregulation of the EndophilinA phosphorylation state accelerates activity-induced neurodegeneration. Given that EndophilinA is connected to at least three Parkinson’s disease genes (LRRK2, Parkin and Synaptojanin), dysfunction of EndophilinA-dependent synaptic macroautophagy may be common in this disorder.
“A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals” by Sandra-Fausia Soukup, Sabine Kuenen, Roeland Vanhauwaert, Julia Manetsberger, Sergio Hernández-Díaz, Jef Swerts, Nils Schoovaerts, Sven Vilain, Natalia V. Gounko, Katlijn Vints, Ann Geens, Bart De Strooper, and Patrik Verstreken in Neuron. Published online September 15 2016 doi:10.1016/j.neuron.2016.09.037