Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders
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ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF-X, TripleTOF 5600+
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Kasper Lage
PROVIDER: MSV000087676 | MassIVE | Mon Jun 21 16:07:00 BST 2021
SECONDARY ACCESSION(S): PXD026845
REPOSITORIES: MassIVE
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Project description:Pintacuda G*, Hsu YH*, Tsafou K, Li KW, Martín JM, Riseman J, Biagini JC, Ching JKT, Mena D, Gonzalez-Lozano MA, Egri SB, Jaffe J, Smit AB, Fornelos N, Eggan KC, Lage K. Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders. Cell Genomics (2023). [DOI: https://doi.org/10.1016/j.xgen.2022.100250] Autism spectrum disorders (ASD) have been linked to genes with enriched expression in the brain, but it is unclear how these genes converge into cell-type-specific networks. We built a protein-protein interaction network for 13 ASD-associated genes in human excitatory neurons derived from induced pluripotent stem cells (iPSCs). The network contains newly reported interactions and is enriched for genetic and transcriptional perturbations observed in individuals with ASDs. We leveraged the network data to show that the ASD-linked brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and to characterize a PTEN-AKAP8L interaction that influences neuronal growth. The IGF2BP1-3 complex emerged as a convergent point in the network that may regulate a transcriptional circuit of ASD-associated genes. Our findings showcase cell-type-specific interactomes as a framework to complement genetic and transcriptomic data, and illustrate how both individual and convergent interactions can lead to biological insights into ASDs.
2023-01-17 | GSE178896 | GEO
Project description: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.
2022-05-09 | MSV000089445 | MassIVE
Project description:There has been sustained clinical and cognitive neuroscience research interest in how network correlates of brain-behavior relationships might be altered in Autism Spectrum Disorders (ASD) and other neurodevelopmental disorders. As previous work has mostly focused on adults, the nature of whole-brain connectivity networks underlying intelligence in pediatric cohorts with abnormal neurodevelopment requires further investigation. We used network-based statistics (NBS) to examine the association between resting-state functional Magnetic Resonance Imaging (fMRI) connectivity and fluid intelligence ability in male children (n = 50) with Autism Spectrum Disorders (ASD; M = 10.45, SD = 1.58 years and in controls (M?=?10.38, SD = 0.96 years) matched on fluid intelligence performance, age and sex. Repeat analyses were performed in independent sites for validation and replication. Despite being equivalent on fluid intelligence ability to strictly matched neurotypical controls, boys with ASD displayed a subnetwork of significantly increased associations between functional connectivity and fluid intelligence. Between-group differences remained significant at higher edge thresholding, and results were validated in independent-site replication analyses in an equivalent age and sex-matched cohort with ASD. Regions consistently implicated in atypical connectivity correlates of fluid intelligence in ASD were the angular gyrus, posterior middle temporal gyrus, occipital and temporo-occipital regions. Development of fluid intelligence neural correlates in young ASD males is aberrant, with an increased strength in intrinsic connectivity association during childhood. Alterations in whole-brain network correlates of fluid intelligence in ASD may be a compensatory mechanism that allows equal task performance to neurotypical peers.
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Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.
2018-12-14 | GSE117776 | GEO
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.
2018-12-14 | GSE107895 | GEO
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.
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Project description:Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.
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