Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

0

Transcriptional dysregulation of synaptic genes in a human iPSC model of major mental disorders

ABSTRACT: Schizophrenia and other psychiatric disorders are postulated to be developmental disorders resulting from synapse dysfunction. How susceptibility genes for major mental disorders could lead to synaptic deficits in humans is not well-understood. Here we generated induced pluripotent stem cells (iPSCs) from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia-1 (DISC1) co-segregated with psychiatric disorders and further produced different isogenic iPSC lines via genetic editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPSC-derived forebrain neurons. Mechanistically, mutant DISC1 dysregulates the expression of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1 and the NCoR1 transcription co-repressor complex. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our study uncovers a novel gain-of-function mechanism through which the psychiatric disorder-relevant mutation affects synaptic functions via transcriptional dysregulation and provides insight into the molecular and synaptic etiopathology of psychiatric disorders. Two patient derived iPSC lines carrying heterozygous 4bp deletion in DISC1 gene and 1 related control were analyzed in biological triplicate

ORGANISM(S): Homo sapiens

SUBMITTER: Kenneth Kosik 

PROVIDER: E-GEOD-57821 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

Json Xml
altmetric image

Publications

Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the biological basis of schizophrenia. Although this hypothesis has gained indirect support from human post-mortem brain analyses and genetic studies, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits  ...[more]

Similar Datasets

Transcriptomics Transcriptional dysregulation of synaptic genes in a human iPSC model of major mental disorders
2014-08-01 | GSE57821 | GEO
Transcriptomics Transcriptome profiling of human neural progenitor cells and neurons with DISC1 interruption
2015-09-14 | E-GEOD-71289 | biostudies-arrayexpress
Proteomics Human Neuron Proteome Altered by Disrupted in schizophrenia 1 (DISC1) Mutations
2021-09-08 | PXD013391 | Pride
Proteomics Endogenous Cell Type-Specific DISC1 Interactomes Reveal Protein Networks Associated to Neurodevelopmental Disorders
2018-07-04 | PXD007103 | Pride
Transcriptomics Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β
2025-04-01 | GSE230632 | GEO
Transcriptomics DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy
2025-02-17 | GSE289385 | GEO
Proteomics Proteomics of rat overexpressing human DISC1 in the dorsal striatum
2018-02-27 | PXD008123 | Pride
Transcriptomics RNA-seq of oligodendroglia progenitor cells(OPCs) isolated from WT and DISC1-Δ3 mice
2022-12-28 | GSE183341 | GEO
Transcriptomics Temporal dysregulation of cortical gene expression in the isolation-reared Wistar rat
2010-06-16 | E-GEOD-19653 | biostudies-arrayexpress
Transcriptomics Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders
2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress