Targeting neural cell senescence reverses neuropsychiatric disorders
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ABSTRACT:
PROVIDER: PRJNA635422 | ENA |
REPOSITORIES: ENA
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Project description:The accumulation of senescent cells behaves as a key driver of several age-related cancers and degenerative diseases of the general population. Whether cellular senescence also contributes to psychiatric diseases is still elusive. We report here the characterization of a zebrafish model of psychiatric disorder resulting from the invalidation of the ppp2r2c gene known to be involved in various psychiatric pathologies in human and encoding a neural specific regulatory subunit of the Protein Phosphatase 2A (PP2A). We found that the behavioral abnormalities of adult ppp2r2c-defficient fish were associated to neural cell senescence and that they can be reversed by invalidating the tp53 gene or by treating the fish with a drug that eliminates senescent cells. A molecule commonly used to treat ADHD patients, the methylphenidate, decreases the number of senescent neural cells both in adult PPP2R2C-defficient fish and in wild-type old fish. At the molecular level, methylphenidate attenuates the DNA damage response. We propose that some of the drugs commonly used in neuropsychiatry such as methylphenidate can prevent the appearance of senescent neural cells and that general strategies to clear senescent cells are promising therapies for common psychiatric disorders.
2022-12-22 | GSE151307 | GEO
Project description:Brain development requires a complex choreography of cell proliferation, specialisation, migration and network formation, guided by the activation and repression of gene expression programs. It remains unclear how this process is disrupted in neuropsychiatric disorders. Here we integrate human genetics with transcriptomic data from the differentiation of human embryonic stem cells into cortical excitatory neurons. This reveals a cascade of transcriptional programs, activated during early corticoneurogenesis in vitro and in vivo, in which genetic variation is robustly associated with neuropsychiatric disorders and cognitive function. Within these early neurogenic programs, genetic risk is concentrated in loss-of-function intolerant (LoFi) genes, capturing virtually all LoFi disease association. Down-regulation of these programs in DLG2 knockout lines delays expression of cell-type identity alongside marked deficits in neuronal migration, morphology and action potential generation, validating computational predictions. These data implicate specific cellular pathways and neurodevelopmental processes in the aetiology of multiple neuropsychiatric disorders and cognition.
2021-10-30 | GSE172199 | GEO
Project description:A complex train of events unfolds during brain development, guided by activation/repression of gene expression programs. It remains unclear how this process is disrupted in disease. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. This reveals a cascade of transcriptional programs activated during early corticoneurogenesis in vitro and in vivo. Genetic variation in these programs is robustly associated with neuropsychiatric disorders and cognitive function, with variants concentrated in loss-of-function intolerant genes. Neurogenic programs also capture schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways activated during pre-natal development underlie disease-relevant deficits in mature neuronal function. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and impairs neuronal migration, morphology and action potential generation, validating predicted deficits. These data implicate specific cellular pathways underlying neurodevelopment in the aetiology of multiple neuropsychiatric disorders and cognition.
2021-11-11 | PXD029526 | Pride
Project description:Brain region- and cell-specific transcriptome and epigenome molecular features are associated with heritability for neuropsychiatric traits. Here, we provide an atlas of chromatin accessibility and gene expression in neuronal and non-neuronal cells across 25 distinct regions across cortical and subcortical areas of the human brain from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions. We further identified variation in alternative promoter-isoform usage and enhancer-promoter interactions across brain regions and found genes with distinct promoter-isoform usage are strongly enriched for neuropsychiatric risk variants. We identified brain region-specific chromatin co-accessibility and gene-coexpression modules that are robustly associated with genetic risk variants for neuropsychiatric disorders. Using an integrative approach, we identify a novel set of genes that is enriched for neuropsychiatric disorders risk variants but is independent of cell-type specific gene expression and annotated pathways. Our results provide a valuable multi-brain region molecular regulation resource and suggest a unique contribution of epigenetic modifications from the subcortical areas to neuropsychiatric disorders.
2022-08-25 | GSE211792 | GEO
Project description:Brain region- and cell-specific transcriptome and epigenome molecular features are associated with heritability for neuropsychiatric traits. Here, we provide an atlas of chromatin accessibility and gene expression in neuronal and non-neuronal cells across 25 distinct regions across cortical and subcortical areas of the human brain from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions. We further identified variation in alternative promoter-isoform usage and enhancer-promoter interactions across brain regions and found genes with distinct promoter-isoform usage are strongly enriched for neuropsychiatric risk variants. We identified brain region-specific chromatin co-accessibility and gene-coexpression modules that are robustly associated with genetic risk variants for neuropsychiatric disorders. Using an integrative approach, we identify a novel set of genes that is enriched for neuropsychiatric disorders risk variants but is independent of cell-type specific gene expression and annotated pathways. Our results provide a valuable multi-brain region molecular regulation resource and suggest a unique contribution of epigenetic modifications from the subcortical areas to neuropsychiatric disorders.
2022-08-25 | GSE211822 | GEO
Project description:DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition
| PRJNA722412 | ENA
Project description:Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts
| PRJNA751578 | ENA
Project description:We describe the first human single-nuclei transcriptomic atlas for substantia nigra (SN), generated by sequencing ~ 17,000 nuclei from matched cortical and SN samples. We show that common genetic risk for Parkinson’s disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression including mitochondrial functioning, protein folding and ubiquitination pathways. We also identified a distinct cell-type association between PD risk and oligodendrocyte-specific expression implicating metabolic and gene expression regulation networks. Beyond PD, we find SN DaNs and GABAergic neurons to be associated with different neuropsychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BP). We identified distinct cortex/SN associations with SCZ genetic risk for both excitatory (synaptic functioning) and dopaminergic neurons (mitochondrial functioning and synaptic signalling). Conditional analyses shows that independent sets of loci associate distinct neuropsychiatric disorders with the same neuronal types. This atlas guides our aetiological understanding by associating SN cell-type expression profiles with specific disease risk.
2020-01-07 | GSE140231 | GEO
Project description:Chromatin accessibility mapping for functional GWAS risk variants of neuropsychiatric and neurodegenerative disorders in hiPSC-derived neural cells
| PRJNA1099272 | ENA
Project description:Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation and survival. Disruptions lead to neurodevelopmental disorders including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1-null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of TGF-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.
2021-08-09 | PXD027798 |