ArticleMolecular psychiatry2021
Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 36 citations in OpenAlex.
- DISC1 Orchestrates Mitochondrial Calcium Overload in Diabetic Encephalopathy Through a Dual Nucleocytoplasmic Mechanism.Biomolecules · 2026Article
- The role of ATF4 in neurons under mitochondrial stress.NAR genomics and bioinformatics · 2026Article
- Transcription Factors in the Pathogenesis of Schizophrenia.Life (Basel, Switzerland) · 2026Review
- ChREBP-β Exacerbates Renal Tubular Disorders Caused by Fructose via ATF4.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- The schizophrenia associated protein DISC1 forms a multivalent tetrameric hub via conserved UVR dimers.Nature communications · 2026Article
- Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β.Science China. Life sciences · 2026Article
- Deciphering the Heterogeneity of Schizophrenia: A Multimodal and Multivariate Neuroimaging Framework for Unveiling Brain-Symptom Relationships and Underlying Subtypes.Schizophrenia bulletin · 2026Article
- The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention.Frontiers in molecular neuroscience · 2026Review
- Tracing the aggregation pathway of the scaffold protein DISC1: Structural implications for chronic mental illnesses.Journal of structural biology: X · 2025Article
- Nootkatone inhibits the progression of glioblastoma by activating the ATF4-CHOP-CHAC1 pathway.Molecular medicine (Cambridge, Mass.) · 2025Article
- Modeling common and rare genetic risk factors of neuropsychiatric disorders in human induced pluripotent stem cells.Schizophrenia research · 2024Review
- Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.bioRxiv : the preprint server for biology · 2024Article
- Defined co-cultures of glutamatergic and GABAergic neurons with a mutation in DISC1 reveal aberrant phenotypes in GABAergic neurons.BMC neuroscience · 2024Article
- Genetics of human brain development.Nature reviews. Genetics · 2024Review
- ATF4 Transcriptionally Activates SHH to Promote Proliferation, Invasion, and Migration of Gastric Cancer Cells.Cancers · 2023Article
- Evidence of DISC1 as an arsenic binding protein and implications regarding its role as a translational activator.Frontiers in molecular biosciences · 2023Article
- Conformational heterogeneity coupled with β-fibril formation of a scaffold protein involved in chronic mental illnesses.Translational psychiatry · 2021Article
- Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders.The international journal of neuropsychopharmacology · 2021Review
- Extending the Horizon of Homology Detection with Coevolution-based Structure Prediction.Journal of molecular biology · 2021Review
- Generation of hypothalamic arcuate organoids from human induced pluripotent stem cells.Cell stem cell · 2021Article
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Authors and funding
14 authors at 6 institutions in 3 countries.
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Abstract
Psychiatric disorders are a collection of heterogeneous mental disorders arising from a contribution of genetic and environmental insults, many of which molecularly converge on transcriptional dysregulation, resulting in altered synaptic functions. The underlying mechanisms linking the genetic lesion and functional phenotypes remain largely unknown. Patient iPSC-derived neurons with a rare frameshift DISC1 (Disrupted-in-schizophrenia 1) mutation have previously been shown to exhibit aberrant gene expression and deficits in synaptic functions. How DISC1 regulates gene expression is largely unknown. Here we show that Activating Transcription Factor 4 (ATF4), a DISC1 binding partner, is more abundant in the nucleus of DISC1 mutant human neurons and exhibits enhanced binding to a collection of dysregulated genes. Functionally, overexpressing ATF4 in control neurons recapitulates deficits seen in DISC1 mutant neurons, whereas transcriptional and synaptic deficits are rescued in DISC1 mutant neurons with CRISPR-mediated heterozygous ATF4 knockout. By solving the high-resolution atomic structure of the DISC1-ATF4 complex, we show that mechanistically, the mutation of DISC1 disrupts normal DISC1-ATF4 interaction, and results in excessive ATF4 binding to DNA targets and deregulated gene expression. Together, our study identifies the molecular and structural basis of an DISC1-ATF4 interaction underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.
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