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Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders

ABSTRACT: Pintacuda G, Hsu YH, Tsafou K, Li KW, Martin JM, Riseman J, Biagini JC, Ching JKT, Gonzalez-Lozano MA, Egri SB, Jaffe JD, Smit AB, Fornelos N, Eggan KC, Lage K. 2022. Sequencing studies of autism spectrum disorders (ASDs) have identified numerous risk genes with enriched expression in the human brain, but it is still unclear how these genes converge into cell type-specific networks and how their encoded proteins mechanistically contribute to ASDs. To address this question, we performed brain cell type-specific interaction proteomics to build a protein-protein interaction network for 13 ASD risk genes in human excitatory neurons derived from iPS cells. The network contains many (>90%) interactions not reported in the literature and is enriched for transcriptionally perturbed genes observed in layer 2/3 cortical neurons of ASD patients, indicating that it can be explored for ASD-relevant biological discovery. We leveraged the network dataset to show that the brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and characterized a PTEN-AKAP8L interaction that influences neuronal growth through the mTOR pathway. The IGF2BP1-3 complex emerges as a point of convergence in the network, and we showed that this complex is involved in a transcriptional circuit concentrating both common and rare variant risk of ASDs. Finally, we found the network itself enriched for ASD rare variant risk, indicating that it can complement genetic datasets for prioritizing additional risk genes. Our findings establish brain cell type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in ASDs and illustrate how both individual and convergent interactions lead to biological insights into the disease.

INSTRUMENT(S): Q Exactive Plus, Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Jacob D. Jaffe

PROVIDER: MSV000089445 | MassIVE | Mon May 09 07:43:00 BST 2022

REPOSITORIES: MassIVE

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Project description:Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. To identify potential A2BP1-dependent differential splicing events in ASD brain, we performed high-throughput RNA sequencing (RNA-Seq) on three autism samples with significant downregulation of A2BP1 (average fold change by quantitative RT-PCR = 5.9) and three control samples with average A2BP1 levels. The list of potential A2BP1-depending differential splicing events in ASD is given in the Supplementary file linked at the foot of this record.

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Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders

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