Exploring protein translation dynamics in autism spectrum disorder-associated mutations

Autism spectrum disorder (ASD) is a complex and highly prevalent neurodevelopmental disorder characterized by significant heterogeneity in genotypes and phenotypes. Recent research has identified dysregulation of protein synthesis as a potential converging mechanism in ASD. To explore altered translation in ASD, we used induced pluripotent stem cell (iPSC)-derived iNeurons and cortical brain organoids. CRISPR/Cas9 technology was employed to introduce ASD-causing mutations in the FMR1, PTEN, and TSC2 genes in iPSCs from healthy donors. These modified iPSCs were then differentiated into either iNeurons or cortical brain organoids. Using label-free data-independent acquisition (DIA), we identified about 8,000 proteins. Principal component analysis (PCA) revealed that mutations in TSC2 and PTEN caused a wide range of consistent changes in both iNeurons and organoids. These changes included up-regulated translation and mitochondrial processes and down-regulated transcriptional processes. Notably, the down-regulated proteins were strongly enriched in genes known to be associated with ASD, indicating that the proteomic data can help explain the broad genetic diversity of ASD. In summary, our integrated proteomic analyses of iPSC-derived iNeurons and organoids shed new light on the pathophysiological processes underlying ASD.