Patrick Lüningschrör, Postdoc in Michael Sendtner’s group at the Institute of Clinical Neurobiology is the lead author of a study on molecular mechanisms in motoneuron disease published in this week’s issue of Nature Communications.
Q: What do you consider the key finding of your study?
Mutations within the human PLEKHG5-gene have been associated to different forms of motoneuron diseases, but the function of the corresponding PLEKHG5 protein within the nervous system remained largely unknown. I think the key finding of our study is that Plekhg5 seems to be an important mediator of synaptic vesicle turnover at motoneuron terminals and that the dysfunction of this mechanism results in motoneuron disease.
Q: How do your results contribute to our understanding of motoneuron diseases and their treatment?
I believe that motoneuron terminals are specifically vulnerable to defects in synaptic vesicle turnover due to their large terminals and large number of synaptic vesicles as compared to other synapses. So far, most research focused on protein turnover in general, but each neuronal-subtype represents a highly specialized cell with a unique protein composition. Given the large number of presynaptic proteins and their complex interplay, the turnover of individual synaptic components needs to be tightly regulated in a timely and spatially confined manner. Defective synaptic components such as synaptic vesicles or structural proteins of the active zone need to be recognized and degraded. I think that this might represent a starting point for therapeutic modulation.
Q: It looks like this project involved collaborations with other researchers in Europe and the US- in which ways do you think this benefited the science?
During our work on the project, Beyenech Binotti from Reinhard Jahn´s lab published that the small GTPase Rab26 specifically directs synaptic vesicles to autophagosomes. We then asked whether Plekhg5-deficient cells might display a diminished activity, which would be explanation for the observed accumulation of synaptic vesicles. Interestingly, the results of our experiments all pointed into the direction that the activity of Rab26 was indeed reduced, but the final proof that Plekhg5 is a guanine exchange factor for Rab26 was still missing. Such assays are done in a cell-free system and the ability of a potential GEF to trigger the GTP-exchange of a certain GTPase is monitored using purified proteins. Reinhard Jahn offered to run these GEF-assays in his lab in Göttingen. The assays were carried out by Beyenech Binotti and Angel-Perez Lara. In the end, it was great to be able to break it down from the organism, to motoneurons and finally to individual molecules.
In general, collaborations with other researchers allowed applying methods and techniques in our study, which would have been very time-consuming and difficult to establish in our lab. Furthermore, working with different labs, which are all experts in their fields, gives the opportunity to look at scientific questions from different perspectives.
Q: What are your plans for the future, both research-wise and personally?
Research-wise the next goal is to get independent funding to set up a research group at our institute. Personally, I would like to continue to contribute to a better understanding of synaptic quality control and homeostasis. As mentioned earlier the pre-synapse contains a large number of components, whose turnover needs to be tightly regulated in a timely and spatially confined manner. Furthermore, neurons need quality control systems to differentiate between functional and non-functional synaptic components. I think that these mechanisms are not only important for motoneuron function, but also play a role in other neurodegenerative diseases and even higher brain function. So, there are still a lot of exciting things to discover.
Lüningschrör P, Binotti B, Dombert B, Heimann P, Perez-Lara A, Slotta C, Thau-Habermann N, R von Collenberg C, Karl F, Damme M, Horowitz A, Maystadt I, Füchtbauer A, Füchtbauer EM, Jablonka S, Blum R, Üçeyler N, Petri S, Kaltschmidt B, Jahn R, Kaltschmidt C, Sendtner M (2017) Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease. Nature Communications 30, 8(1): 678. doi: 10.1038/s41467-017-00689-z.