Chemico-genetic Analysis of Native Autism Proteomes Reveals Shared Biology Predictive of Functional Modifiers

Abstract

AbstractOne of the main drivers of autism spectrum disorder (ASD) are risk alleles within hundreds of genes, which may interact within shared biological processes through as-yet unclear mechanisms. Here we develop a high-throughput genome-editing-mediated approach to target 14 high-confidence ASD genes within the mouse brain for proximity-based proteomics of endogenous interactomes. The resulting interactomes are enriched for human genes dysregulated in the brain of ASD patients and reveal unexpected, but highly significant, interactions with other lower confidence ASD-risk gene products, positing new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the disorder. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two ASD models, demonstrating new functional interactions that modulate mechanisms of their dysregulation. Together, our results reveal native protein-interaction networks in ASD, providing new inroads for understanding its cellular neurobiology.