Schizophrenia risk proteins ZNF804A and NT5C2 interact in cortical neurons

The zinc finger protein 804A (ZNF804A) and the 5′‐nucleotidase cytosolic II (NT5C2) genes are amongst the first schizophrenia susceptibility genes to have been identified in large‐scale genome‐wide association studies. ZNF804A has been implicated in the regulation of neuronal morphology and is requi...

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Bibliographic Details
Published in:	The European journal of neuroscience Vol. 59; no. 8; pp. 2102 - 2117
Main Authors:	Aabdien, Afra, Sichlinger, Laura, Borgel, Zoe, Jones, Madeleine R., Waston, Iain A., Gatford, Nicholas J. F., Raval, Pooja, Tanangonan, Lloyd, Powell, Timothy R., Duarte, Rodrigo R. R., Srivastava, Deepak P.
Format:	Journal Article
Language:	English
Published:	France Wiley Subscription Services, Inc 01-04-2024 John Wiley and Sons Inc
Subjects:	5'-Nucleotidase - genetics 5'-Nucleotidase - metabolism Adenosine kinase AMP Clinical and Translational Neuroscience dendrite dendritic spine Dendritic spines Genome-Wide Association Study Genomes Genotypes HEK293 Cells Humans Kinases Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - metabolism Mental disorders Neural stem cells Neurons - physiology Neurosciences NT5C2 Nucleotidase Progenitor cells Protein biosynthesis Proteins psychosis Research Report Schizophrenia Schizophrenia - genetics Schizophrenia - metabolism synapse Zinc finger proteins ZNF804A ZNF804A dendrite dendritic spine synapse NT5C2 psychosis
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Summary:	The zinc finger protein 804A (ZNF804A) and the 5′‐nucleotidase cytosolic II (NT5C2) genes are amongst the first schizophrenia susceptibility genes to have been identified in large‐scale genome‐wide association studies. ZNF804A has been implicated in the regulation of neuronal morphology and is required for activity‐dependent changes to dendritic spines. Conversely, NT5C2 has been shown to regulate 5′ adenosine monophosphate‐activated protein kinase activity and has been implicated in protein synthesis in human neural progenitor cells. Schizophrenia risk genotype is associated with reduced levels of both NT5C2 and ZNF804A in the developing brain, and a yeast two‐hybrid screening suggests that their encoded proteins physically interact. However, it remains unknown whether this interaction also occurs in cortical neurons and whether they could jointly regulate neuronal function. Here, we show that ZNF804A and NT5C2 colocalise and interact in HEK293T cells and that their rodent homologues, ZFP804A and NT5C2, colocalise and form a protein complex in cortical neurons. Knockdown of the Zfp804a or Nt5c2 genes resulted in a redistribution of both proteins, suggesting that both proteins influence the subcellular targeting of each other. The identified interaction between ZNF804A/ZFP804A and NT5C2 suggests a shared biological pathway pertinent to schizophrenia susceptibility within a neuronal cell type thought to be central to the neurobiology of the disorder, providing a better understanding of its genetic landscape. Recent studies indicate a physical interaction between schizophrenia‐associated genes ZNF804A and NT5C2. This study reveals that these proteins co‐localise and interact in HEK293 cells and primary rat cortical neurons. Knockdown experiments reveal mutual influences on subcellular targeting, and may indicate that these two proteins function as a complex to regulate neuronal processes.
Bibliography:	Edited by: Michel Barrot ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0953-816X 1460-9568 1460-9568
DOI:	10.1111/ejn.16254