Das_2025_ACS.Chem.Neurosci__

Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental condition characterized by difficulties in social interactions and communication, alongside repetitive behaviors and restricted interests. Its etiology is a complex etiology involving genetic, environmental, and epigenetic factors, with significant contributions from mutations in synaptic proteins, including neuroligins (NLGNs), neurexins (NRXNs), and SHANK family proteins. Structural changes caused by mutations in these proteins can lead to synaptic dysfunction, disrupt scaffolding, and impact neuronal circuitry, which reflects the symptoms of ASD. The purpose of this study is to compile the most recent findings regarding protein structure and how specific mutations in these proteins contribute to ASD. This systematic review conducted a comprehensive analysis of research published from 2014 to 2024, collected from the Web of Science and Scopus databases, and the protein structure was collected from the Protein Data Bank. Research that employed cryogenic electron microscopy, nuclear magnetic resonance spectroscopy, and other advanced structural biology methods for molecular modeling was prioritized. After evaluating the findings of the final 40 studies, mutations in the synaptic proteins SHANK3 (G54W, L47P, G250D, R12C, L68P), SHANK2 (S557N), NLGN3 (R451C), NLGN4 (R101Q), and NRXN1 destabilize protein structure, reduce synaptic adhesion, and disrupt neurotransmitter clustering, which influences ASD symptoms. Advanced techniques reveal the molecular structure underlying ASD in animal models, which provides interventions like gene transplantation that can mitigate the effects of these mutations. However, challenges persist in finding treatments for the numerous molecular mechanisms contributing to ASD, emphasizing the need for further research into the structure of all ASD-related proteins.