Exploring altered translation in Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a complex, prevalent neurodevelopmental disorder with significant
\ngenotype and phenotype heterogeneity. Recent studies suggest dysregulated protein synthesis as a
\nkey mechanism in ASD. This study explores altered translation in ASD using induced pluripotent stem
\ncells (iPSCs), a promising tool for disease modelling. We introduced ASD-relevant mutations in FMR1,
\nPTEN, and TSC2 into iPSCs from healthy donors via CRISPR/Cas9. The iPSCs were then differentiated
\ninto iNeurons and cortical organoids, and their proteomes were analysed using mass spectrometry.
\nTSC2 and PTEN mutants showed similar profiles in both models, while FMR1 showed differences only
\nin organoids, not in iNeurons. GO enrichment analysis revealed increased abundance of proteins
\nassociated with mitochondrial processes, such as cellular respiration and protein synthesis, reflecting
\nmTORC1 hyperactivation due to PTEN and TSC2 mutations. Downregulated proteins were related to
\ntranscriptional and epigenetic regulation. Notably, dysregulated proteins included genes linked to ASD
\n(SFARI gene list), emphasizing the proteomic data's relevance. These findings are expected to
\nelucidate ASD's molecular underpinnings, covering both specific mutations and shared alterations
\namong different ASD-related mutations.