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ABSTRACT:
PROVIDER: PRJNA1134707 | 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: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 complex psychiatric disorder encompassing a range of symptoms and etiology dependent upon the interaction of genetic and environmental factors. Several risk genes, such as DISC1, have been associated with schizophrenia as well as bipolar disorder (BPD) and major depressive disorder (MDD), consistent with the hypothesis that a shared genetic architecture could contribute to divergent clinical syndromes. The present study compared gene expression profiles across three brain regions in post-mortem tissue from matched subjects with schizophrenia, BPD or MDD and unaffected controls. Post-mortem brain tissue was collected from control subjects and well-matched subjects with schizophrenia, BPD, and MDD (n=19 from each group). RNA was isolated from hippocampus, Brodmann Area 46, and associative striatum and hybridized to U133_Plus2 Affymetrix chips. Data were normalized by RMA, subjected to pairwise comparison followed by Benjamini and Hochberg False Discovery Rate correction (FDR). Samples derived from patients with schizophrenia exhibited many more changes in gene expression across all brain regions than observed in BPD or MDD. Several genes showed changes in both schizophrenia and BPD, though the magnitude of change was usually larger in schizophrenia. Several genes that have variants associated with schizophrenia were found to have altered expression in multiple regions of brains from subjects with schizophrenia. Continued evaluation of circuit-level alterations in gene expression and gene-network relationships may further our understanding of how genetic variants may be influencing biological processes to contribute to psychiatric disease. Pre-frontal cortex, striatum and hippocampus were obtained from subjects with schizophrenia, bipolar disorder, major depressive disorder and matched controls.
2014-01-11 | E-GEOD-53987 | biostudies-arrayexpress
Project description:Synaptic dysfunction has been implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BP). In this study, we used quantitative mass-spectrometry to carry out deep and unbiased profiling of the proteome of synapses purified from the dorsolateral prefrontal cortex of 35 controls and 35 cases each with SCZ or BP. Compared to controls, SCZ and BP synapses showed substantial and similar proteomic alterations. Network and gene set enrichment analyses revealed upregulation of proteins associated with autophagy and certain vesicle transport pathways, and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. We also uncovered evidence for dysregulation of some of the same pathways (e.g., upregulation of vesicle transport, downregulation of mitochondrial and ribosomal proteins) in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered risk gene for both SCZ and BP. Our work provides novel biological insights and hypotheses into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these debilitating neuropsychiatric disorders.
| MSV000090320 | MassIVE
Project description:Bipolar disorder (BD) is a highly heritable and heterogeneous mental illness whose manifestations often include impulsive and risk-taking behavior. This particular phenotype suggests that abnormal striatal function could be involved in BD etiology, yet most transcriptomic studies of this disorder have concentrated on cortical brain regions. We report the first transcriptome profiling by RNA-Seq of the human dorsal striatum comparing bipolar and control subjects. Differential expression analysis and functional pathway enrichment analysis were performed to identify changes in gene expression that correlate with BD status. Further co-expression and enrichment analyses were performed to identify sets of correlated genes that show association to BD. Total RNA samples were isolated from 36 postmortem dorsal striatum subjects (18 bipolar and 18 control) and sequenced. One outlier sample was removed and 35 samples (18 bipolar and 17 control) were analyzed.
2016-08-10 | E-GEOD-80336 | biostudies-arrayexpress
Project description:We used microarrays to identify the differently expressed genes in disease model for bipolar disorder and schizophrenia.
2018-07-10 | GSE116820 | GEO