Summary: <\/strong>A precision functional genomics study successfully mapped the biological timing and cellular consequences of a major schizophrenia-associated gene. The research investigates ZNF804A, the very first risk gene identified from human genomic data, and pinpoints its peak activity during a critical early developmental window.<\/p>\n By utilizing CRISPR-Cas9 gene editing to suppress ZNF804A in developing cortical neurons, neuroscientists exposed a direct structural link between localized protein production and hyper-excitable synaptic signaling. This breakthrough bridges a long-standing knowledge gap in psychiatric medicine, translating abstract genetic risk into tangible neurobiological pathways.<\/p>\n Key Facts<\/strong><\/p>\n Source: <\/strong>King\u2019s College London<\/p>\n Researchers at King\u2019s College London\u00a0have\u00a0identified\u00a0the biological nature and timing of\u00a0changes in\u00a0human\u00a0cortical\u00a0neurons caused by altering activity of a schizophrenia-associated gene in developing human neurons. <\/strong><\/p>\n This discovery links a genetic\u00a0risk\u00a0factor to cellular changes in neurons; an essential step for understanding the neurobiology of this\u00a0mental illness\u00a0and developing future treatments.\u00a0<\/p>\n Schizophrenia is estimated to be one of the most heritable psychiatric conditions, with a strong developmental aspect. Large scale human genomic studies have\u00a0identified\u00a0many genetic variants which are thought to increase the likelihood of schizophrenia.\u00a0\u00a0<\/p>\n However, the link\u00a0between these genetic\u00a0risk\u00a0variants and the underlying\u00a0neurobiology\u00a0of schizophrenia is less well understood.\u00a0Addressing\u00a0this knowledge gap provides\u00a0vital information\u00a0that\u00a0could\u00a0ultimately help\u00a0develop therapies\u00a0for the disorder. \u00a0\u00a0<\/p>\n This new research, published in Science Advances, from neuroscientists at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), starts to bridge the knowledge gap between genetics and their neural consequences that\u00a0lead\u00a0to symptoms of schizophrenia.\u00a0<\/p>\n Professor\u00a0Deepak Srivastava, Professor of Molecular Neuroscience\u00a0at\u00a0IoPPN\u00a0King\u2019s College London and\u00a0joint senior author on the paper said: \u201cWhile\u00a0previous\u00a0large-scale\u00a0genetic studies have\u00a0identified\u00a0genetic\u00a0risk\u00a0factors\u00a0for schizophrenia, they\u00a0don\u2019t\u00a0tell you when in development that gene is\u00a0active or\u00a0which cell type it\u2019s expressed in.\u00a0To get\u00a0at this information\u00a0we needed to use precision functional genomics.\u201d<\/p>\n Relatively little\u00a0is known about the mechanism of\u00a0the first schizophrenia-related gene to be\u00a0identified\u00a0from genomic data, ZNF804A.\u00a0The study\u00a0identifies\u00a0a specific type of neuron where ZNF804A is most active in an important developmental window.\u00a0<\/p>\n The findings also\u00a0establish\u00a0a novel link\u00a0between two previously\u00a0identified\u00a0cellular processes associated with the gene: synaptic regulation and protein production regulation.\u00a0<\/p>\n Dr Laura Sichlinger,\u00a0Research Fellow at University of Pennsylvania and\u00a0first author on the study said: \u201cSchizophrenia is\u00a0a highly complex\u00a0disorder. It has both a genetic and environmental\u00a0component.<\/p>\n \u201cThere are 287 loci so far\u00a0identified\u00a0by genomic studies in humans. To be able to understand what the genes\u00a0normally do in neurons is a step forward in understanding the biology of the disorder.\u201d\u00a0<\/p>\n Brain development is a carefully coordinated process triggered by sequentially activated genes\u00a0that choreograph the precise maturation of\u00a0different types\u00a0of neurons and support cells in the brain. To understand developmental disorders, it is essential to identfy the\u00a0timing of gene activation.\u00a0\u00a0<\/p>\n The study confirmed that ZNF804A is most active\u00a0early in development, consistent with\u00a0previous\u00a0studies that showed it to be highly expressed in the brain during the second trimester of neurodevelopment.\u00a0\u00a0<\/p>\n The\u00a0new\u00a0research uncovered that ZNF804A\u00a0was most active in\u00a0glutamatergic neurons in this developmental\u00a0period. Crucially, this helped the researchers focus their investigation on this type of neuron, at this\u00a0particular developmental\u00a0stage.\u00a0<\/p>\n To understand how ZNF804A contributes to the underlying\u00a0neurobiology\u00a0and\u00a0ultimately symptoms\u00a0of schizophrenia, researchers\u00a0prevented the gene from functioning\u00a0as it\u00a0would\u00a0normally\u00a0in these glutamatergic neurons. To do this they employed a gene-editing approach called CRISPR-Cas9.<\/p>\n This method works by cutting out part of the DNA in a specific gene,\u00a0meaning it will be less able to be translated in its corresponding protein.\u00a0Essentially, it\u00a0will be able to do less of its normal function in the cell.\u00a0<\/p>\n By looking at\u00a0the\u00a0changes\u00a0that happened\u00a0after\u00a0interfering\u00a0with\u00a0ZNF804A,\u00a0researchers could infer what the gene might be doing in development and what types of cellular processes might be altered in neurons with schizophrenia-related mutations.\u00a0<\/p>\n Scientists then used a microscope to look at the junctions, called synapses, between neurons with supressed ZNF804A gene activity. These junctions are run by a series of proteins sitting on the neuronal membrane. Some sit on the neuron sending the signal; some on the neuron receiving the signal. Changes in the numbers of\u00a0these\u00a0synaptic proteins\u00a0can\u00a0impact\u00a0how\u00a0the neurons send and receive signals.\u00a0<\/p>\n The microscopy images revealed that there were more proteins at the synapses between the glutamatergic neurons, suggesting they might be more electrically excitable than normal.\u00a0<\/p>\n This was confirmed by chemically stimulating\u00a0the neurons causing them to be\u00a0more\u00a0electrically active. The neurons which had less ZNF804A gene responded more than normal ones.\u00a0<\/p>\n Some of the proteins that sit at the synapse can be created through a process called \u2018protein translation\u2019 in which a biological blueprint\u00a0(called mRNA) of the protein is read in, and the corresponding protein is produced.\u00a0Normally if more proteins are being made in a neuron, scientists will see evidence of more translation.\u00a0<\/p>\n Neurons\u00a0are cells with\u00a0distinctive shapes, much like trees with many branching projections. The junctions between neurons can form at many parts of the neuron but often lie\u00a0on\u00a0the smallest branches called dendrites. To get proteins to these synapses, neurons must transport\u00a0ribosomes (the\u00a0machinery that builds\u00a0new\u00a0proteins) to\u00a0the ends of the dendrite branch.<\/p>\n This\u00a0provides\u00a0an ideal way to regulate how much protein is made at specific neuronal junctions: by controlling\u00a0where the ribosomes\u00a0are,\u00a0and how many are\u00a0available\u00a0to make new proteins.\u00a0<\/p>\n The schizophrenia risk gene\u00a0ZNF804A\u00a0has previously been associated with cells\u2019 protein translation machinery. However, it was unknown how this related to links to synapses and signalling between neurons.\u00a0\u00a0\u00a0<\/p>\n The new study found that the neurons with impaired ZNF804A had more synapses and they had more protein\u00a0production\u00a0locally in their dendrites, providing a crucial link\u00a0between these two cellular functions of ZNF804A. This paves the way towards a comprehensive mechanistic understanding of the role this gene plays in neuronal development.\u00a0<\/p>\n Professor\u00a0Anthony Vernon,\u00a0Professor of Neuropsychopharmacology at IoPPN, King\u2019s College London and\u00a0joint senior author on the paper said: \u201cWe want to stress that these specific genetic manipulations of developing neurons do not mimic the full complement of genetic risk linked to schizophrenia. Rather, they are a tool that allow us to understand what specific risk genes, in this case, ZNF804A control in a cell and developmental timepoint specific manner.<\/p>\n \u201cThis in turn illuminates the biological processes and pathways that may be affected by specific schizophrenia-linked genetic mutations, such as those in ZNF804A. The next step is to use these tools at scale to ask whether and how the diverse array of risk genes linked to schizophrenia may converge on similar pathways and produce similar phenotypes.\u201d<\/p>\n Funding: <\/strong>This research was funded by\u00a0the UK Medical Research Council\u00a0(MRC Centre for Neurodevelopmental Disorders,\u00a0MRC Doctoral Training Partnership), Royal Society UK,\u00a0Brain and\u00a0Behavior\u00a0Foundation\u00a0and the\u00a0National Centre for the Replacement, Refinement and Reduction of Animals in Research.\u00a0<\/p>\n A<\/strong>: Think of schizophrenia as an incredibly complex jigsaw puzzle with 287 separate edge pieces scattered across the genome. Knowing that<\/em> a gene causes a risk doesn\u2019t tell a doctor how to treat it. ZNF804A<\/strong> was the very first piece of the puzzle ever discovered, yet its inner workings remained a mystery. By successfully tracking down exactly when it fires and showing that it prevents brain cells from becoming electrical hotheads, King\u2019s College London has given science a concrete blueprint to start linking all the other risk genes together.<\/p>\n<\/div>\n A<\/strong>: Neurons are shaped like miniature trees with long, branching arms called dendrites. To communicate, they build communication junctions, synapses, at the very tips of these branches. Normally, ZNF804A acts like a strict traffic warden, controlling how many protein-building factories (ribosomes) make it to those branches. When you break that gene, the factories flood the dendrites, churning out an uncontrolled excess of local proteins. This overcrowded grid makes the synapses far more electrically excitable than they should be, scrambling the brain\u2019s internal signaling.<\/p>\n<\/div>\n A<\/strong>: No, and it is crucial to temper expectations. This study did not use CRISPR as a cure, but rather as an elite research tool to intentionally break a specific mechanism so scientists could watch what went wrong. Because ZNF804A does its critical work during the second trimester of fetal development, an adult\u2019s brain architecture has already been cast. However, by explicitly showing that the target is a hyper-active protein factory in glutamatergic neurons, it gives drug developers a clear bullseye to design future medications that can quiet these hyper-excitable pathways.<\/p>\n<\/div>\n<\/div>\n Author:\u00a0<\/strong>Franca Davenport<\/a>\n
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<\/picture>Key Questions Answered:<\/h3>\n
Editorial Notes:<\/h3>\n
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About this schizophrenia and genetics research news<\/h2>\n
Source:\u00a0<\/strong>King\u2019s College London<\/a>
Contact:\u00a0<\/strong>Franca Davenport \u2013 King\u2019s College London
Image:\u00a0<\/strong>The image is credited to Neuroscience News<\/p>\n