Biology subjects

Duarte, R. R.

Publications and source records attributed to Duarte, R. R..

7 recordsLinked to original sources

bioRxiv2025

Transcriptome-informed brain cartography of polygenic risk and association with brain structure in major psychiatric disorders

Psychiatric disorders are complex, polygenic conditions characterized by patterned structural brain alterations. Whether these changes reflect transcriptional dysregulation driven by genetic risk remains unclear. We introduce a novel imaging-transcriptomics framework that integrates transcriptome-wide association studies (TWAS) with brain transcriptomic atlases to predict macroscale structural brain abnormalities across seven disorders: ADHD, ASD, AN, BD, MDD, OCD, and schizophrenia (SCZ). We generated disorder-specific Gene Expression-based Disorder Associated Risk (GEDAR) maps and assessed their spatial correlation with observed brain alterations thereby establishing a structured approach to map polygenic transcriptional risk onto macroscale brain phenotypes. We found significant transcriptomic-anatomical correlations in MDD (cortical and subcortical), SCZ (subcortical), and ADHD (subcortical), indicating that regional transcriptional vulnerability might contribute to varying extents to the anatomical expression of genetic risk in these disorders. Pathway enrichment analysis on genetically predicted differentially expressed genes for those disorders where we found spatial correlations between GEDAR maps and observed structural changes revealed immune-related processes as dominant in MDD and SCZ, and neurodevelopmental pathways in ADHD. ASD, AN, OCD, and cortical SCZ lacked significant associations. Importantly, spatial transcriptomic-anatomical alignment did not scale with between-disorder differences in heritability, pointing instead toward additional influences like developmental timing or environmental interactions. These findings underscore the potential and limitations of imaging transcriptomics as a framework for bridging the gap between genetic architecture and systems-level brain changes in psychiatric disorders.

neuroscience↗

bioRxiv2024

Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

ZNF804A was amongst the first genes robustly associated with schizophrenia based on findings from large-scale genomic studies. Previous research has implicated ZNF804A in the regulation of gene expression and synaptic function, but the role of this gene in neurodevelopment and in schizophrenia pathogenesis remains unclear. To study its function during neurodevelopment, we generated isogenic human induced pluripotent stem cells (hiPSCs) with reduced ZNF804A expression, differentiated them into developing cortical glutamatergic neurons and studied their transcriptomic, synaptic and protein signatures. Mutant neurons showed modest evidence changes in gene expression. However, high-content confocal imaging revealed increased excitatory synapse density in mutant neurons. Cell-compartment specific proteomic analysis further revealed that mutant neurons had higher levels of ribosomal and translational proteins within neurites, and high-content imaging confirmed increased local protein synthesis efficiency. Overall, these results demonstrate that in human developing cortical glutamatergic neurons, ZNF804A regulates excitatory synapse formation potential via increased local protein translation.

neuroscience↗

bioRxiv2023

Estradiol regulates local synthesis of synaptic proteome via sex-specific mechanisms.

Estrogens, specifically 17{beta}-estradiol (estradiol), can modulate synaptic function by regulating the expression and localisation of synaptic proteins. However, the mechanisms underlying estradiols regulation of synaptic protein expression, and whether if they occur in a sex specific manner, is not well understood. In this study, using sex-specific hippocampal slice cultures and mixed-sex primary hippocampal neurons, we investigated whether local protein synthesis is required for estradiol- induced synaptic protein expression. Estradiol rapidly increased the rate of protein synthesis and the number of actively translating ribosomes along dendrites and near synapses in both male and female hippocampal neurons. Importantly, these effects occurred independently of gene transcription. Moreover, estradiol also increased the abundance of nascent proteins localised to synapses, independently of gene transcription. Specifically, estradiol increased the synaptic expression of GluN2B- containing N-methyl-D-aspartate receptors and PSD-95 in male and female hippocampus. Mechanistically, mTOR signalling was required for estradiol-induced increases in overall local protein synthesis only in male but not female hippocampus. Consistent with this, mTOR signalling mediated estradiol increases in GluN2B in male, but not female, hippocampus. Conversely, mTOR inhibition, blocked estradiol-induced increased PSD-95 expression in both male and female hippocampus. Collectively, these data suggest that the rapid modulation of local protein synthesis by estradiol is required for changes in the synaptic proteome in male and female hippocampus, and that the requirement of the mTOR signalling pathway in these effects occur in both a sex-specific and protein-dependent manner, with this signalling pathway have a greater role in male compared to female hippocampus.

neuroscience↗

bioRxiv2021

Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells

Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). This link is particularly well established in the case of schizophrenia. Converging lines of evidence from human and animal model studies have suggested that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 hour) treatment with either interferon-gamma (IFN{gamma}; 25 ng/l) or interleukin (IL)-1{beta} (10 ng/l), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFN{gamma}-treated control lines (compared to untreated controls), and 1980 DEGs in IFN{gamma}-treated SZ lines (compared to untreated SZ lines). Of these, 359 genes responded differently to IFN{gamma} treatment in SZ relative to control lines, which were enriched for genes differentially expressed in adult SZ cases and in pathways related to the regulation of antigen processing, neuronal post-synaptic density, and the presynapse. There were no differentially expressed genes in the IL-1{beta}-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1{beta} impacts immune function and neuronal differentiation. Collectively, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFN{gamma} treatment compared to control NPCs; b) IL-1{beta} may be less relevant to NPC cultures than IFN{gamma} and c) the genes differentially regulated in schizophrenia lines are primarily mitochondrial, loss-of-function, pre- and post-synaptic genes. Our findings particularly highlight early synaptic development as a key target for future research into the mechanisms of association between maternal immune activation and schizophrenia risk. Highlights* There is a significant transcriptional response to IFN{gamma} treatment in human induced cortical neural progenitor cells (NPCs) * Differential expression implicates mitochondrial complex genes in this IFN{gamma}-dependent response, which are underexpressed in response to treatment in schizophrenia (SZ) NPCs. * SZ NPCs do not upregulate pre- and post-synaptic genes in response to IFN{gamma} as much as control NPCs * IL-1{beta} may be less relevant to NPC cultures than IFN{gamma} due to low IL1 receptor expression in NPCs.

neuroscience↗

bioRxiv2020

The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk

Telomere shortening is one hallmark of cell ageing that can limit the proliferative capacity of cell populations and increase risk for age-related disease. It has been hypothesized that short telomeres, and subsequently a limited proliferative capacity of hippocampal progenitor cells, could contribute to smaller hippocampal volumes and impaired cognition, amongst psychiatric disorder patients. The current study employed a systematic, multidisciplinary approach which aimed to model the effects of telomere shortening on human hippocampal neurogenesis, and to explore its relationship with cognition and psychiatric disorder risk. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Aged progenitors demonstrated shorter telomeres (p<0.05), and reduced rates of cell proliferation, as marked by bromodeoxyuridine staining (p<0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene set enrichment analysis revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts showed a significant overlap with genes regulating cognitive function and risk for schizophrenia and bipolar disorder. Collectively, our results suggest that reductions in adult hippocampal neurogenesis, caused by telomere shortening, could represent a cellular mechanism contributing to age-related cognitive impairment and psychiatric disorder risk.

neuroscience↗

bioRxiv2019

Schizophrenia risk from locus-specific human endogenous retroviruses

Schizophrenia genome-wide association studies highlight the substantial contribution of risk attributed to the non-coding genome where human endogenous retroviruses (HERVs) are encoded. These ancient viral elements have previously been overlooked in genetic and transcriptomic studies due to their poor annotation and repetitive nature. Using a new, comprehensive HERV annotation, we found that the fraction of the genome where HERVs are located (the retrogenome) is enriched for schizophrenia risk variants, and that there are 148 disparate HERVs involved in susceptibility. Analysis of RNA-sequencing data from the dorsolateral prefrontal cortex of 259 schizophrenia cases and 279 controls from the CommonMind Consortium showed that HERVs are actively expressed in the brain (n = 3,979), regulated in cis by common genetic variants (n = 1,759), and differentially expressed in patients (n = 81). Convergent analyses implicate LTR25_6q21 and ERVLE_8q24.3h as HERVs of etiological relevance to schizophrenia, which are co-regulated with genes involved in neuronal and mitochondrial function, respectively. Our findings provide a strong rationale for exploring the retrogenome and the expression of these locus-specific HERVs as novel risk factors for schizophrenia and potential diagnostic biomarkers and treatment targets.

neuroscience↗

bioRxiv2018

Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

Genome-wide significant variants associated with combined risk for major psychiatric disorders on chromosome 10q24 affect the expression of the cytosolic 5-nucleotidase II (NT5C2, cN-II) in population controls, implicating it as a psychiatric susceptibility gene. Risk alleles are associated with reduced expression of this gene in the developing and adult brain, but the resulting neurobiological risk mechanisms remain elusive. In this study, we provide further evidence for the association of NT5C2 with psychiatric disorders, and use a functional genetics approach to gain a deeper understanding of the function of this risk gene in the nervous system. NT5C2 expression was significantly reduced in the post-mortem brain of schizophrenia and bipolar disorder patients, and its protein predominately expressed in neurons within the adult brain. Using human neural progenitor cells (hNPCs), we found that NT5C2 expression peaked at the neural progenitor state, where the encoded protein was ubiquitously distributed through the cell. NT5C2 knockdown in hNPCs elicited transcriptomic changes associated with protein translation, that were accompanied by regulation of adenosine monophosphate-activated protein kinase (AMPK) signalling and ribosomal protein S6 (rpS6) activity. To identify the effect of reduced neuronal NT5C2 expression at a systems level, we knockdown its homologue, CG32549, in Drosophila melanogaster CNS. This elicited impaired climbing behaviour in the model organism. Collectively, our data implicate NT5C2 expression in risk for psychiatric disorders and in Drosophila melanogaster motility, and further suggest that risk is mediated via regulation of AMPK signalling and protein translation during early neurodevelopment.

neuroscience↗