Structural Insights into Protein Mutations Related to Autism Spectrum Disorders: A Systematic Review.

Scientists reviewed 40 studies about protein changes that may cause autism symptoms. They found that specific changes in brain proteins called SHANK3, SHANK2, and neuroligins make these proteins unstable and disrupt how brain cells communicate. These protein problems affect how nerve connections work in the brain, which may explain autism symptoms. While gene therapy shows promise as a future treatment, developing effective treatments remains challenging due to autism's complexity.

This systematic review analyzed 40 studies from 2014-2024 examining how structural changes in autism-related proteins contribute to ASD symptoms. The research focused on synaptic proteins including SHANK3, SHANK2, neuroligins (NLGN3, NLGN4), and neurexins (NRXN1) using advanced structural biology techniques. Specific mutations were identified that destabilize protein structure, reduce synaptic adhesion, and disrupt neurotransmitter clustering. These structural changes lead to synaptic dysfunction and altered neuronal circuitry that may underlie ASD symptoms.

The review highlights potential for gene-based interventions but acknowledges significant challenges in developing treatments due to the complex molecular mechanisms involved in autism.

Findings advance understanding of molecular mechanisms in autism but don't yet translate to clinical treatments. May inform future genetic testing approaches and gene therapy development. Emphasizes need for continued research into protein structure-function relationships in autism.

Based on animal model research with unclear human translation. Treatment challenges persist due to numerous molecular mechanisms in ASD. The review doesn't specify methodological quality assessment of included studies or address potential publication bias.

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.