Project 55.2: Investigating local protein synthesis deficits in schizophrenia

Genome wide association studies (GWAS) link variation in the ZNF804A gene to increased risk

for schizophrenia and bipolar disorder. However, the function(s) of the protein encoded by the

ZNF804A gene remains largely unknown and putative disease causing mechanisms cannot be

established. Whilst ZNF804A may function as a transcription factor, work from our group

revealed that the protein encoded by ZNF804A resided at synapses. Furthermore, it was

required for both the maintenance of synapse number and the ability of a cell to remodel its

synapses in response to synaptic stimulation (activity-dependent signalling). More recently, yet

another role for ZNF804A has been described, linking it to the control of cellular protein

synthesis. Work from our lab has now linked these lines of evidence to suggest that ZNF804A

is important for controlling activity-dependent protein synthesis.

These data suggest a testable hypothesis that ZNF804A plays a critical role in mediating

activity-dependent changes in the synaptic proteome. The aim of this project is therefore to

investigate the consequence of manipulating ZNF804A gene expression levels on how a

neuron responds to activity-dependent stimulation. This will be achieved using a range of

biochemical and cutting edge imaging techniques (including super-resolution imaging) to

determine how activity-dependent protein synthesis is impacted and what synaptic proteins are

affected. These studies will be the first to determine whether deficits in activity-dependent

synthesis of synaptic proteins is a mechanism contributing to synaptic dysfunction in

schizophrenia and provide a potential mechanistic explanation linking genetic variation in

ZNF804A and psychosis risk.