Abstract
Autism spectrum disorder (ASD) is a genetically heterogeneous disorder. Sequencing studies have identified hundreds of risk genes for autism spectrum disorder (ASD), but the signaling networks of genes at the protein level remain largely unexplored, which can provide insight into previously unknown individual and convergent disease pathways in the brain. To address this gap, we used neuron- specific proximity-labeling proteomics (BioID) to identify protein-protein interaction (PPI) networks of 41 ASD-risk genes. Network analysis revealed the combined 41 risk gene PPI network map had more shared connectivity between unrelated ASD-risk genes than represented in existing public databases. We identified common pathways between established and uncharacterized risk genes, including synaptic transmission, mitochondrial/metabolic processes, Wnt signaling pathways, ion channel activity and MAPK signaling. Investigation of the mitochondrial and metabolic network using gene knockouts revealed a functional hub in neurons for multiple risk genes not previously associated with this pathway. Further, we identified that the uncharacterized ASD-risk gene PPP2R5D localizes to the synapse, which is disrupted by patient de novo missense mutations. Investigation of de novo missense variants of additional synaptic ASD-risk genes demonstrated that changes in PPI networks can capture synaptic transmission deficits. The neuronal 41 ASD-risk gene PPI network map also revealed enrichment for an additional 112 ASD-risk genes and human brain cell types implicated in ASD pathology. Interestingly, clustering of ASD-risk genes based on their PPI network connectivity identified multiple gene groups that correlate mutation-type to clinical behavior scores. Together, our data reveal that using PPI networks to map ASD risk genes can identify previously unknown individual and convergent neuronal signaling networks, provide a method to assess the impact of patient variants, and reveal new biological insight into disease mechanisms.
Main Highlights
Neuron-specific protein interaction screening of 41 ASD-risk genes to identify new disease mechanisms at the protein level
High connectivity between multiple unrelated ASD-risk genes at the protein interaction level
PPI networks show disease-relevant pathways including synaptic transmission, metabolic pathways, Wnt signaling, ion channel activity, MAPK signaling
Metabolic pathways, such as TCA cycle and pyruvate metabolism, are altered in neurons by multiple ASD-risk genes not previously linked to this pathway
Novel localization of uncharacterized ASD-risk gene PPP2R5D at the synapse, which is disrupted by de novo mutations identified in patients
Clustering of ASD-risk genes based on PPI connectivity identifies multiple gene groups that show correlation between mutation-type and clinical behavior scores, revealing the importance of understanding PPI networks in ASD
Competing Interest Statement
The authors have declared no competing interest.
