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A foundational atlas of autism protein interactions reveals molecular convergence [scRNA-seq]

ABSTRACT: A foundational atlas of autism protein interactions reveals molecular convergence [scRNA-seq]

PROVIDER: PRJNA1202137 | ENA |

REPOSITORIES: ENA

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A foundational atlas of autism protein interactions reveals molecular convergence [CUT&Tag]

Project description:A foundational atlas of autism protein interactions reveals molecular convergence [CUT&Tag]

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A foundational atlas of autism protein interactions reveals molecular convergence [CUT&Tag]

Project description:Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.

2024-12-25 | GSE285273 | GEO

A foundational atlas of autism protein interactions reveals molecular convergence [scRNA-seq]

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High-throughput Functional Analysis of Autism Genes in Zebrafish Identifies Convergence in Dopaminergic and Neuroimmune Pathways

Project description:Investigation of convergence and divergence of different Autism Risk genes at the molecular level, in the brain of zebrafish ASD mutants at 6 days-post-fertilizitation (dpf)

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Rescue of oxytocin response and social behavior in a rodent model of autism

Project description:One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. To possibly circumvent this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin which regulate aspects of social behavior in mammals. However, whether genetic risk factors might predispose to autism due to modification of oxytocinergic signaling remains largely unknown. Here, we report that an autism-associated mutation in the synaptic adhesion molecule neuroligin-3 (Nlgn3) results in impaired oxytocin signaling in dopaminergic neurons and in altered social novelty responses in mice. Surprisingly, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3KO mice with a novel, highly specific, brain-penetrant inhibitor of MAP-kinase interacting kinases resets mRNA translation and restores oxytocin and social novelty responses. Thus, this work identifies an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, and oxytocinergic signaling. Focus on such common core plasticity elements might provide a pragmatic approach to reduce the heterogeneity of autism phenotypes. Ultimately, this would allow for mechanism-based stratification of patient populations to increase the success of therapeutic interventions.

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