An iPSC model reveals the underlying mechanism of transcriptional and synaptic dysregulation in mental disorders
Prof. Mingjie Zhang and his collaborators Prof. Ming from the University of Pennsylvania have reported a DISC1 (Disrupted-in-schizophrenia 1) and ATF4 (Activating Transcription Factor 4) interaction in iPSC (induced pluripotent stem cell)-derived neurons with a DISC1 mutation. Their findings, published in Molecular Psychiatry, reveal the underlying mechanisms linking the genetic lesion and functional phenotypes of psychiatric disorders.
Many mental disorders, including schizophrenia, are neurodevelopmental disorders arising from genetic aberrations and transcriptional dysregulation. A rare frameshift mutation in DISC1, a genetic risk factor implicated in several psychiatric disorders, has been shown to exhibit aberrant gene expression and defective synaptic functions. However, how DISC1 regulates gene expression was remained unclear.
ATF4, a DISC binding partner, is found to be more abundant in the nucleus of DISC1 mutant human cortical neurons and regulates the expression of a collection of dysregulated genes involved in synaptic function. When overexpressed in control neurons, the phenotypes recapitulates the synaptic deficits seen in DISC1 mutant neurons, whereas heterozygous ATF4 knockout rescues the transcription and synaptic deficits in DISC1 mutant neurons.
The high-resolution atomic structure of DISC1-ATF4 complex has also revealed that mutation in DISC1 disrupts the normal DISC1-ATF4 interaction, resulting in excessive ATF4 binding to DNA targets and deregulated gene expression.
These findings identify the molecular and structural interactions between DISC1 and ATF4 underlying the transcription and synaptic dysregulation in an iPSC model of mental disorders and provide insight into the pathogenesis of psychiatric disorders.
Wang X, Ye F, Wen Z, Guo Z, Yu C, Huang WK, Rojas Ringeling F, Su Y, Zheng W, Zhou G, Christian KM, Song H, Zhang M, Ming GL. Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.Mol Psychiatry. 2019 Aug 23. doi: 10.1038/s41380-019-0485-2.