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Aug 18, 2014

Flawed Gene a Hub of Dysregulation and Synaptic Corruption

Flawed Gene a Hub of Dysregulation and Synaptic Corruption

Immune-based staining of a mature iPSC cortex neuron shows synapse markers (red, green) and the cell's nucleus (blue). [Hongjun Song, Ph.D., Johns Hopkins University]

  • A gene long associated with schizophrenia and subsequently studied in rodent brain has now been scrutinized in human neurons. These neurons, derived from induced pluripotent stem cells (iPSCs), made for a powerful “disease in a dish” model, allowing scientists to trace the outward rippling of transcriptional dysregulation caused by a central genetic flaw, the gene DISC1 (Disrupted in Schizophrenia-1).

    Most major mental disorders, such as schizophrenia, are thought to be caused by a complex interplay of multiple genes and environmental factors. However, studying rare cases of a single disease-linked gene that runs in a family can provide shortcuts to discovery.

    Decades ago, researchers traced a high prevalence of schizophrenia in a Scottish clan to mutations in DISC1. Now researchers based at Johns Hopkins report that they have revisited DISC1. This time, however, they used stem cell technology, inducing patients’ skin cells to revert into stem cells before coaxing them to differentiate into neurons. The researchers, led by Hongjun Song, Ph.D., studied iPSCs from four members of an American family affected by DISC1-linked schizophrenia and genetically related mental disorders.

    The researchers presented their results August 18 in Nature, in an article entitled, “Synaptic dysregulation in a human iPS cell model of mental disorders.”

    “We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons,” the authors wrote. “Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons.”

    Strikingly, the iPSC-induced neurons expressed 80% less of the protein made by the DISC1 gene in family members with the mutation, compared to members without the mutation. These mutant neurons showed deficient cellular machinery for communicating with other neurons at synapses. The researchers traced these deficits to errant expression of genes known to be involved in synaptic transmission, brain development, and key extensions of neurons where synapses are located.

    The “many genes” that were abnormally expressed included 89 previously linked to schizophrenia, bipolar disorder, depression, and other major mental disorders. This was surprising, the researchers said, as DISC1’s role as a hub that regulates expression of many genes implicated in mental disorders had not previously been appreciated.

    The clincher came when researchers experimentally produced the synapse deficits by genetically engineering the DISC1 mutation into otherwise normal iPSC neurons—and, conversely, corrected the synapse deficits in DISC1 mutant iPSC neurons by genetically engineering a fully functional DISC1 gene into them. This established that the DISC1 mutation, was, indeed the cause of the deficits.

    “Our results illustrate how genetic risk, abnormal brain development, and synapse dysfunction can corrupt brain circuitry at the cellular level in complex psychiatric disorders,” explained Dr. Song.

    “Our findings from studying human forebrain neurons derived from a collection of patient iPS cells and different isogenic lines suggests a model in which susceptibility genes for major psychiatric disorders could affect synaptic function via large-scale transcriptional dysregulation in human neurons,” concluded the authors of the Nature study. “Our collection of isogenic iPS cell lines and robust cellular phenotypes also provide a platform for mechanism-guided exploration of therapeutic compounds in correcting synaptic defects of human neurons and for nonbiased large-scale screens.”


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