Schizophrenia risk ZNF804A interacts with its associated proteins to modulate dendritic morphology and synaptic development

Abstract

Schizophrenia (SZ) is a devastating brain disease that affects about 1% of world population. Among the top genetic associations, zinc finger protein 804A (ZNF804A) gene encodes a zinc finger protein, associated with SZ and biolar disorder (BD). Copy number variants (CNVs) of ZNF804A have been observed in patients with autism spectrum disorders (ASDs), anxiety disorder, and BD, suggesting that ZNF804A is a dosage sensitive gene for brain development. However, its molecular functions have not been fully determined. Our previous interactomic study revealed that ZNF804A interacts with multiple proteins to control protein translation and neural development. ZNF804A is localized in the cytoplasm and neurites in the human cortex and is expressed in various types of neurons, including pyramidal, dopaminergic, GABAergic, and Purkinje neurons in mouse brain. To further examine the effect of gene dosage of ZNF804A on neurite morphology, both knockdown and overexpression of ZNF804A in primary neuronal cells significantly attenuate dendritic complex and spine formation. To determine the factors mediating these phenotypes, interestingly, three binding proteins of ZNF804A, galectin 1 (LGALS1), fasciculation and elongation protein zeta 1 (FEZ1) and ribosomal protein SA (RPSA), show different effects on reversing the deficits. LGALS1 and FEZ1 stimulate neurite outgrowth at basal level but RPSA shows no effect. Intriguingly, LGALS1 but not FEZ1, reverses the neurite outgrowth deficits induced by ZNF804A knockdown. However, FEZ1 and RPSA but not LGALS1, can ameliorate ZNF804A overexpression-mediated dendritic abnormalities. Thus, our results uncover a critical post-mitotic role of ZNF804A in neurite and synaptic development relevant to neurodevelopmental pathologies.

Zinc in Cognitive Impairment and Aging

“…Cognitive deficits in many neuropsychiatric disorders are thought to be related to dendritic spines or neurite growth [ 196 , 197 , 198 , 199 ]. In the primary cortical neurons of ZFP804A knockdown rats, the neurite growth and the density of dendritic spines are significantly reduced, and the upregulation and downregulation of ZFP804A significantly damage the dendritic morphology; furthermore, different ZFP804A binding proteins show varying levels of reversal of dendritic and synaptic defects [ 200 ]. A recent study showed that ZFP804A was necessary for NPC proliferation and neuronal migration, and the overexpression of the gene encoding neurogranin (an SZ risk gene and the target of ZFP804A) can offset the migration defect caused by ZFP804A knockdown [ 193 ].…”

“…Regulate people's language, reading, and cognitive abilities, and participate in the regulation of cognitive impairment-related diseases [193,195,[200][201][202]…”

Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation

“…SNP rs1344704 is located in the second intron of the ZNF804A gene, being the first to show a significant association with increased susceptibility to schizophrenia in a GWAS (O'Donovan et al, 2008 ), which has been consistently replicated in larger subsequent ones (Ripke et al, 2014 ; Steinberg et al, 2011 ; Williams et al, 2011 ), also extending to bipolar disorder, mainly in the context of European populations. ZNF804A is known to be highly expressed in brain tissues, specifically in the cytoplasm, neurites and dendritic spines in the human cortex (with higher density in the cingulate cortex), as well as in various types of mouse neurons (including pyramidal, dopaminergic and glutamatergic ones) (Dong, Mao, Chen, Yoon, & Mao, 2021 ).…”

Schizophrenia Risk Proteins ZNF804A and NT5C2 Interact at Synapses

“…Similarly, ZFP804A (rodent homologue) was found to be enriched in synaptic fractions, and to localise to dendritic spines, where the majority of excitatory synapses occur in the mammalian brain (Deans et al, 2017). Consistent with a role for the encoded zinc finger protein at synapses, knockdown or knockout of Zfp804A resulted in a reduction of dendritic spine density (Deans et al, 2017;Huang et al, 2020), whereas an increase in spine density was observed when the full length or shorter disease-associated isoform of the protein was overexpressed in cortical neurons (Dong et al, 2021;Zhou et al, 2020). Moreover, activity-dependent remodelling of dendritic spines was impaired in cortical neurons with reduced ZNF804A expression levels (Deans et al, 2017).…”

“…A recent interactome study using a yeast two-hybrid assay has indicated that ZNF804A interacts with multiple proteins, including NT5C2 (Zhou et al, 2018). Follow up studies have demonstrated that ZNF804A forms a complex with several predicted interactors to regulate neuronal morphology (Dong et al, 2021). Interestingly, it was noted that NT5C2 is the only potential interacting protein for ZNF804A, encoded by a GWAS-supported gene (Zhou et al, 2018).…”