Project 55.2: Investigating local protein synthesis deficits in schizophrenia

全基因组关联研究将ZNF804A基因的变异与精神分裂症和双相情感障碍的风险增加联系在一起。然而，ZNF804A基因编码的蛋白的功能(S)在很大程度上仍不清楚，推测的致病机制也不能确定。虽然ZNF804A可能作为转录因子发挥作用，但我们小组的工作发现，ZNF804A编码的蛋白质位于突触。此外，它既是维持突触数量所必需的，也是细胞对突触刺激(活动依赖信号)做出反应时重塑突触的能力所必需的。最近，ZNF804A的另一个角色被描述，将其与细胞蛋白质合成的控制联系起来。我们实验室的工作现在已经将这些证据联系在一起，表明ZNF804A对于控制活性依赖的蛋白质合成是重要的。这些数据表明了一个可检验的假说，即ZNF804A在介导突触蛋白质组中的活性依赖的变化中发挥了关键作用。因此，该项目的目的是调查操纵ZNF804A基因表达水平对动脉瘤对活动依赖刺激的反应的后果。这将使用一系列生化和尖端成像技术(包括超分辨率成像)来确定依赖活动的蛋白质合成是如何受到影响的，以及哪些突触蛋白质受到影响。这些研究将首次确定突触蛋白活性依赖的合成缺陷是否是导致精神分裂症突触功能障碍的机制，并提供一种潜在的机制解释，将ZNF804A的遗传变异与精神病风险联系起来。

Genome wide association studies (GWAS) link variation in the ZNF804A gene to increased riskfor schizophrenia and bipolar disorder. However, the function(s) of the protein encoded by theZNF804A gene remains largely unknown and putative disease causing mechanisms cannot beestablished. Whilst ZNF804A may function as a transcription factor, work from our grouprevealed that the protein encoded by ZNF804A resided at synapses. Furthermore, it wasrequired for both the maintenance of synapse number and the ability of a cell to remodel itssynapses in response to synaptic stimulation (activity-dependent signalling). More recently, yetanother role for ZNF804A has been described, linking it to the control of cellular proteinsynthesis. Work from our lab has now linked these lines of evidence to suggest that ZNF804Ais important for controlling activity-dependent protein synthesis.These data suggest a testable hypothesis that ZNF804A plays a critical role in mediatingactivity-dependent changes in the synaptic proteome. The aim of this project is therefore toinvestigate the consequence of manipulating ZNF804A gene expression levels on how aneuron responds to activity-dependent stimulation. This will be achieved using a range ofbiochemical and cutting edge imaging techniques (including super-resolution imaging) todetermine how activity-dependent protein synthesis is impacted and what synaptic proteins areaffected. These studies will be the first to determine whether deficits in activity-dependentsynthesis of synaptic proteins is a mechanism contributing to synaptic dysfunction inschizophrenia and provide a potential mechanistic explanation linking genetic variation inZNF804A and psychosis risk.