Here are our introductory comments:
Hello everyone, and welcome to today’s webinar. My name is Sandra Apler; I’m a Syngap parent and the founder of the European Syngap organisation Leon and Friends.We are very excited to have this webinar with our sister organization in the US, Syngap Research Fund. Our talk for today is “Investigating the functional single-cell biology of SynGAP1 pathways”I have the pleasure to introduce today’s speaker, Dr. Michael Courtney.Michael Courtney is a Senior Research Fellow at the Turku Bioscience Centre in Finland. The main focus of his work has been to develop and apply optical methods to investigate neuronal responsivity and the underlying signalling networks. His research group initially focused on the roles of the JNK and p38 cell stress signalling pathways in models of neurological diseases. His team identified novel druggability of protein scaffolding mechanisms mediating NMDA receptor-evoked pathological signalling pathways acting via p38 MAP kinase, by the development of first-in-class inhibitor tool compounds targeting NOS1AP. These showed efficacy in multiple neurological disease models. Meanwhile, protein-protein interaction methods were developed to help identify additional opportunities for druggability and to facilitate compound screening. Population snapshot omic data acquired from disease models and their responsiveness to compounds demonstrated the need to quantify the dynamics of signaling networks at the single cell level.
To address this, his lab developed a minimally invasive optical perturbation and measurement pipeline implemented on high-throughput automation platforms. The pipeline allows simultaneous monitoring and optogenetic control of signalling circuit dynamics in individual cells in an interacting network, as well as in situ measurement of pathway kinetics. Single-cell omic analysis algorithms can be adapting to analyse the multiplexed dynamic datasets acquired. This identifies the distinct responsiveness profiles of individual cells. This insight can help interpret the consequences of disease-associated protein and signalling network disruption, and the potential druggability of specific targets, aberrant pathways and cellular phenotypes.
His lab recently began applying this approach to investigate pathways that are either regulating or regulated by SynGAP1, together with the impact of drugs of relevance to SynGAP syndrome. One ongoing project, funded by Leon and friends e.V., is to identify the endogenous RasGEF that counteracts SynGAP1 function, as a potential drug target for treatment of SynGAP1 hypofunction. Funding is being sought for additional projects to help understand the normal and aberrant activities of wild type and missense mutants of SynGAP1.
We would like to take this opportunity again to thank you for your commitment to our Syngap1 children!A recorded version of this webinar will be available on the SRF website under Webinars on the Family menu, and on the Leon and friends website.
Dr. Michael Courtney is a researcher at the Neuronal Signaling Lab and Turku Screening Unit at the Turku Bioscience Center in Finland. He starts off the talk with the goals of his lab: identifying protein signaling networks and druggable sites within these networks, as well as developing methods for precise measurement and manipulation of single cells over time. Dr. Courtney explains how cell signaling works and how single cell responses are heterogenous based on cell type. He then talks about the effects of statins, old drugs which can inhibit small GTPases like Ras which are prevalent in SYNGAP1. In neurons, statins reduce ERK, extracellular signal-regulated kinase, and calcium responses, but unexpectedly activate JNK signaling, a kinase which is associated with negative consequences. He closes the webinar explaining split protein complementation methods, including fluorescence complementation and proximity labeling. These methods can be used to investigate the effects of sequence variants on SYNGAP1 localization and stability, as well as to identify the protein dynamics associated with SYNGAP1 variants. In the future, this information could help determine locations for drug sites.