Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders

Pintacuda, Greta; Hsu, Yu-Han H.; Tsafou, Kalliopi; Li, Ka Wan; Martín, Jacqueline M.; Riseman, Jackson; Biagini, Julia C.; Ching, Joshua K.T.; Mena, Daya; Gonzalez‐Lozano, Miguel A.; Egri, Shawn B.; Jaffe, Jacob D.; Smit, August B.; Fornelos, Nadine; Eggan, Kevin; Lage, Kasper

doi:10.1016/j.xgen.2022.100250

Cited by 26 publications

(43 citation statements)

References 90 publications

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“…We find that genes near noncoding elements with an excess of rare, recessive variants in cases compared to controls include both known ASD-associated genes and previously unassociated genes. Strikingly, proteins encoded by both ASD-associated and previously unassociated genes are known to interact, mirroring recent studies that identify convergent effects on protein networks across multiple, distinct genetic models of ASD (Paulsen et al, 2022; Pintacuda et al, 2023; Li et al, 2023). Many of these previously unassociated genes are dosage-sensitive, known to play critical roles in neurodevelopment, or mutated in severe developmental disorders (Table 1, Fig.…”

Section: Discussionmentioning

confidence: 72%

Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk

Shin,

Song,

Kosicki

et al. 2023

Preprint

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Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior.

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Section: Discussionmentioning

confidence: 72%

Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk

Shin,

Song,

Kosicki

et al. 2023

Preprint

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“…Here, Pintacuda et al. 1 create human neuronal protein-protein interaction (PPI) networks for a subset of ASD risk genes. By experimentally probing ASD-related PPIs in human stem-cell-derived neurons, the authors generated an unprecedented resource.…”

Section: Main Textmentioning

confidence: 99%

“…Pintacuda et al. 1 perform proteomics in induced human neurons and identify more than 1,000 interactions, 90% of which were not previously reported, emphasizing the importance of cell-type- and isoform-specific protein interactions in ASD.…”

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confidence: 99%

Neuronal protein interaction networks in autism spectrum disorder

2023

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“…More than a thousand of candidate genes are listed in the Simons Foundation Autism Research Initiative (SFARI) database (https://gene.sfari.org), and rather than a single mutation, accumulation of deleterious alleles and copy number variants may underlie the pathological process among affected individuals (Manoli and State, 2021). Recent genome wide association studies of large ASD cohorts robustly identified hundreds of candidate genes that fall in two main convergent neurobiological mechanisms, namely 'gene expression regulation' or 'neuronal communication, signalling or plasticity' (De Rubeis et al, 2014;Satterstrom et al, 2020;Pintacuda et al, 2023). G protein-coupled receptors (GPCRs) are master regulators of these convergent mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…Downstream intracellular signalling network leads to integrated cellular processes, translation of specific mRNAs (Musnier et al, 2012;León et al, 2014;Tréfier et al, 2018) and gene transcription via the transcription factor cAMPresponsive element binding protein (CREB), among many others. Globally, GPCRs are key master upstream regulators of Wnt/β-catenin, ERK, PKC, Pi3K/Akt, CREB, PTEN and mTOR intracellular pathways that are convergently dysregulated in ASD (O'Roak et al, 2012;Gazestani et al, 2019;Pintacuda et al, 2023). In an attempt to estimate their potential as master regulators of genes involved in ASD, we confronted 'Kyoto Encyclopedia of Genes and Genomes' (KEGG) pathways, 'Reactome' pathways, 'Gene Ontology' (GO) terms and our knowledge (supporting information ) to the 1045 ASD candidate genes from the SFARI list.…”

Section: Introductionmentioning

confidence: 99%

Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders

Annamneedi

Gora

Dudas

et al. 2023

Preprint

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Autism spectrum disorders (ASD) are diagnosed in 1/100 childbirth worldwide, based on two core symptoms, deficits in social interaction and communication and stereotyped behaviours. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors that mediate the transfer of extracellular signals to convergent intracellular signalling and downstream cellular responses that are dysregulated in ASD. Despite hundreds of GPCRs are expressed in the brain, only 23 GPCRs are genetically associated to ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR, vasopressin V1A, V1B, metabotropic glutamate mGlu5, mGlu7, GABAB, dopamine D1, D2, D3, serotoninergic 5-HT1B, β2-adrenoceptor, cholinergic M3, adenosine A2A, A3, angiotensin AT2, cannabinoid CB1, chemokine CX3CR1, orphan GPR37, GPR85 and olfactory OR1C1, OR2M4, OR2T10, OR52M1. Here, we review the therapeutical potential of these 23 GPCRs, in addition to 5-HT2A, 5-HT6 and 5-HT7 for their relevance to ASD. We discuss their genetic association with ASD, the effects of their genetic and pharmacological manipulation in animal models and humans, their existing pharmacopeia towards core symptoms of ASD and rank them based on these evidences. Among these 23 GPCRs, we highlight that OTR, V1A, mGlu5, D2, 5-HT2A, CB1, and GPR37 are the best therapeutic targets. We conclude that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD and their therapeutic potential has only begun as multiple GPCRs could mitigate ASD.

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Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders

Cited by 26 publications

References 90 publications

Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk

Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk

Neuronal protein interaction networks in autism spectrum disorder

Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders

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