Network and Co-Complex Representations Identify Distinct Components of the SynGAP Protein Environment
Year: 2026
Type: conference-paper
Abstract: SYNGAP1-related disorder is predicted to occur in 6 per 100,000 births and is associated with intellectual disability, epilepsy and behavioural features, yet no disease-modifying treatment is available [1–3]. Within REPO-RARE, a mechanism-based drug-repurposing initiative for monogenic rare diseases, this subproject investigates the protein environment of synaptic Ras GTPase-activating protein (SynGAP). In mice, selective loss of SynGAP’s catalytic activity does not reproduce the neuronal hyperexcitability and increased seizure susceptibility caused by Syngap1 haploinsufficiency [4,5], suggesting that non-catalytic, potentially organisational functions contribute to the phenotype. To identify proteins beyond SynGAP’s canonical postsynaptic Ras/Rap regulation, we generated a first-neighbour protein–protein interaction network using REPO4EU’s Drugst.One DREAM tool [6,7] and compared it with two low-confidence, machine-learning-predicted hu.MAP3.0 co-complexes from the EMBL-EBI Complex Portal [8,9]. Topology-based pruning using a subnetwork participation degree threshold of 0.257, followed by community detection, produced a 26-node subnetwork. This topology-prioritized subnetwork showed no overlap with the predicted co-complexes and contained proteins associated with synaptic adhesion, cytoskeletal regulation, vesicle-related processes and neuronal excitability. We annotated candidates across both representations using published SynGAP-specific evidence from neuronal systems. This prioritised CTNND2 from the topology-derived subnetwork and ANKS1B from the predicted co-complexes. CTNND2 deficiency reduces synaptic SynGAP abundance [10], whereas ANKS1B binds SynGAP directly and functionally interacts with Syngap1 dosage in regulating developmental neuronal-network activity [11,12]. The representations therefore identify distinct candidate components of the SynGAP protein environment. This analysis prioritizes CTNND2-dependent SynGAP localization and ANKS1B–SynGAP binding for experimental validation and subsequent network-guided evaluation of approved drugs capable of modulating these processes.
Institutions: Maastricht University, Akdeniz University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W7204154409