Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1134699 | ENA |
REPOSITORIES: ENA
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Project description:Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. To determine the neurobiological functions of AKAP11 and the consequences of its absence, we conducted multi-omic analyses of Akap11 mutant mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose loss leads to dramatically elevated PKA expression and phosphorylation, especially in synapses. Transcriptomic analysis shows extensive gene expression changes throughout the brain, including prominent decreases in synapse-related genes sets. Gene expression is especially affected in spiny projection neurons of the striatum, a brain region implicated in motivation, cognition and psychiatric disorders. In vivo, real-time measurements of PKA activity in ventral striatum of Akap11-/- mice revealed constitutively elevated kinase activity, which distorts dopamine to PKA signaling. Our work reveals the molecular basis of circuit dysfunction in a genetically valid model of psychotic disorder.
2025-07-11 | GSE272098 | GEO
Project description:Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. To determine the neurobiological functions of AKAP11 and the consequences of its absence, we conducted multi-omic analyses of Akap11 mutant mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose loss leads to dramatically elevated PKA expression and phosphorylation, especially in synapses. Transcriptomic analysis shows extensive gene expression changes throughout the brain, including prominent decreases in synapse-related genes sets. Gene expression is especially affected in spiny projection neurons of the striatum, a brain region implicated in motivation, cognition and psychiatric disorders. In vivo, real-time measurements of PKA activity in ventral striatum of Akap11-/- mice revealed constitutively elevated kinase activity, which distorts dopamine to PKA signaling. Our work reveals the molecular basis of circuit dysfunction in a genetically valid model of psychotic disorder.
2025-07-11 | GSE272097 | GEO
Project description:Loss-of-function mutations in Akap11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. We conducted multi-omic analysis of Akap11 mutant mouse brains, and report that AKAP11 interacts with multiple proteins involved in signaling and proteostasis. In Akap11+/- and Akap11-/- synapses, PKA protein levels were markedly elevated, and many proteins (eg GluA1) were hyperphosphorylated at PKA sites. Akap11 mutant brains showed extensive transcriptomic changes, prominently in synapse-related gene-sets and most profoundly in neurons of the striatum, a brain region implicated in motivation, cognition and psychiatric disorders. Widespread misexpression and differential phosphorylation of neuromodulation-related genes indicated perturbed function and altered organization of the striatum. Our work reveals the molecular mechanism and a potential circuit basis of brain dysfunction in a genetically valid model of psychotic disorder.
2025-09-04 | GSE306677 | GEO
Project description:Bipolar disorder (BD) is a complex psychiatric condition usually requiring long-term treatment. Lithium (Li) remains the most effective mood stabilizer for BD, yet it benefits only a subset of patients, and its precise mechanism of action remains elusive. Exome sequencing has identified AKAP11 (A-kinase anchoring protein 11) as a shared risk gene for BD and schizophrenia (SCZ). Given that both the AKAP11-Protein Kinase A (PKA) complex and Li target and inhibit Glycogen Synthase Kinase-3 beta (GSK3β), we hypothesize that Li may partially normalize the transcriptomic and/or epigenomic alterations observed in heterozygous AKAP11-knockout (Het-AKAP11-KO) iPSC-derived neurons. In this study, we employed genome-wide approaches to assess the effects of Li on the transcriptome and epigenome of human iPSC-derived Het-AKAP11-KO neuronal culture. We show that chronic Li treatment in this cellular model upregulates key pathways that were initially downregulated by Het-AKAP11-KO, several of which have also been reported as downregulated in synapses of BD and SCZ post-mortem brain tissues. Moreover, we demonstrated that Li treatment partially rescues certain transcriptomic alterations resulting from Het-AKAP11-KO, bringing them closer to the WT state. We suggest two possible mechanisms underlying these transcriptomic effects: (1) Li modulates histone H3K27ac levels at intergenic and intronic enhancers, influencing enhancer activity and transcription factor binding, and (2) Li enhances GSK3β serine 9 phosphorylation, impacting WNT/β-catenin signaling and downstream transcription. These findings underscore Li's potential as a therapeutic agent for BD and SCZ patients carrying AKAP11 loss-of-function variants or exhibiting similar pathway alterations to those observed in Het-AKAP11-KO models.
2025-09-29 | GSE290454 | GEO
Project description:Bipolar disorder (BD) is a complex psychiatric condition usually requiring long-term treatment. Lithium (Li) remains the most effective mood stabilizer for BD, yet it benefits only a subset of patients, and its precise mechanism of action remains elusive. Exome sequencing has identified AKAP11 (A-kinase anchoring protein 11) as a shared risk gene for BD and schizophrenia (SCZ). Given that both the AKAP11-Protein Kinase A (PKA) complex and Li target and inhibit Glycogen Synthase Kinase-3 beta (GSK3β), we hypothesize that Li may partially normalize the transcriptomic and/or epigenomic alterations observed in heterozygous AKAP11-knockout (Het-AKAP11-KO) iPSC-derived neurons. In this study, we employed genome-wide approaches to assess the effects of Li on the transcriptome and epigenome of human iPSC-derived Het-AKAP11-KO neuronal culture. We show that chronic Li treatment in this cellular model upregulates key pathways that were initially downregulated by Het-AKAP11-KO, several of which have also been reported as downregulated in synapses of BD and SCZ post-mortem brain tissues. Moreover, we demonstrated that Li treatment partially rescues certain transcriptomic alterations resulting from Het-AKAP11-KO, bringing them closer to the WT state. We suggest two possible mechanisms underlying these transcriptomic effects: (1) Li modulates histone H3K27ac levels at intergenic and intronic enhancers, influencing enhancer activity and transcription factor binding, and (2) Li enhances GSK3β serine 9 phosphorylation, impacting WNT/β-catenin signaling and downstream transcription. These findings underscore Li's potential as a therapeutic agent for BD and SCZ patients carrying AKAP11 loss-of-function variants or exhibiting similar pathway alterations to those observed in Het-AKAP11-KO models.
2025-09-29 | GSE290452 | GEO
Project description:The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. We also show significant downregulation of pathways related to ribosome structure and function, a pathway also altered in BD and SCZ post-mortem brain tissues and heterozygous Akap11-KO mice synapse proteomics. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.
2025-05-01 | GSE263850 | GEO
Project description:The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. We also show significant downregulation of pathways related to ribosome structure and function, a pathway also altered in BD and SCZ post-mortem brain tissues and heterozygous Akap11-KO mice synapse proteomics. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.
2025-05-01 | GSE263847 | GEO
Project description:The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. We also show significant downregulation of pathways related to ribosome structure and function, a pathway also altered in BD and SCZ post-mortem brain tissues and heterozygous Akap11-KO mice synapse proteomics. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.
2025-05-01 | GSE263845 | GEO
Project description:Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes (Akap11, Dagla, Gria3, Grin2a, Sp4, Srrm2, Zmym2). While all studied brain regions were affected, the striatum and the thalamus emerged as key brain regions of convergence. Striatum showed downregulation of synapse- and oxidative phosphorylation-related gene sets in all models. In the thalamus, mutants separated into two groups based on transcriptomic phenotype: synapse-related gene sets were upregulated in mutants with only schizophrenia and bipolar association, and were downregulated in mutants that are associated with developmental delay/intellectual disability in addition to schizophrenia. Overall, our meta-analysis reveals convergence and divergence in brain transcriptomic phenotype in these schizophrenia genetic models, supports the involvement of striatal disturbance and synapse dysfunction in schizophrenia, and points to a key role of the thalamus.
2025-08-29 | GSE299704 | GEO