Project 55.2: Investigating local protein synthesis deficits in schizophrenia

全基因组关联研究（GWAS）将ZNF 804A基因变异与精神分裂症和双相情感障碍风险增加联系起来。然而，ZNF 804A基因编码的蛋白质的功能在很大程度上仍不清楚，推测的致病机制也无法建立。虽然ZNF 804A可能作为一个转录因子发挥作用，但我们小组的工作表明，ZNF 804A编码的蛋白质位于突触中。此外，它是维持突触数量和细胞对突触刺激（活动依赖性信号）的反应重塑突触的能力所必需的。最近，ZNF 804A的另一个作用被描述，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起来，表明ZNF 804A在控制活动依赖性蛋白质合成方面很重要。这些数据提出了一个可验证的假设，即ZNF 804A在介导突触蛋白质组的活动依赖性变化中起着关键作用。因此，本项目的目的是研究操纵ZNF 804A基因表达水平的结果，即ZNF 804A基因对活性依赖性刺激的反应。这将通过一系列生物化学和尖端成像技术（包括超分辨率成像）来实现，以确定活动依赖性蛋白质合成如何受到影响以及哪些突触蛋白受到影响。这些研究将首次确定突触蛋白活性依赖性合成的缺陷是否是导致精神分裂症突触功能障碍的机制，并提供了一个潜在的机制解释，将ZNF 804A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.