Publication Date
8-9-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-51037-x
PMID
39122707
PMCID
PMC11316102
PubMedCentral® Posted Date
8-9-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Proteome, Disease Models, Animal, Mice, Humans, Brain, Proteomics, Autistic Disorder, Autism Spectrum Disorder, Phenotype, Gene Editing, Male, Genetic Predisposition to Disease, Mice, Inbred C57BL, Female, CRISPR-Cas Systems, Neuroscience, Molecular neuroscience
Abstract
One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.