Project 55.2: Investigating local protein synthesis deficits in schizophrenia

点击翻译按钮获取中文摘要

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.