Association between polymorphism rs2421943 of the <scp>insulin‐degrading</scp> enzyme and schizophrenia: Preliminary report

Ambrozová, Laura; Zeman, Tomáš; Janout, Vladimí­r; Janoutová, Jana; Lochman, Jan; Šerý, Omar

doi:10.1002/jcla.24949

Cited by 2 publications

(1 citation statement)

References 48 publications

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“…Of the 11 proteins, the predicted or experimentally observed RBFOX1-mediated upregulation matched the changes in the embryonic dataset for eight proteins: CBLN2, CD34, DPYSL2, FTH1, IDE, MAPT, SNCB, TTBK1, which were all associated with NPDs and comorbidities and in the case of CBLN2, FTH1, and IDE -with observed social deficits (see also Chapter 4.1.). The presence of the insulindegrading enzyme IDE, which has been associated with AD and SCZ (Ambrozova et al, 2023), provides another line of evidence for the connection between brain disorders, insulin signalling, and inflammation (see Chapters 1.2.1, 1.3.2). These insights suggest that a transient RBFOX1 change might have occurred subsequently to MIA that may have led to long-lasting consequences on the synaptic proteome and NPD-relevant behavioural endophenotypes.…”

Section: Domain Modelmentioning

confidence: 99%

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Yotova

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Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects of biological sex and age. Risk factors influencing brain development and signalling include prenatal inflammation and genetic variation. This dissertation aimed to build upon these findings by combining behavioural, molecular, and neuromorphological investigations in mouse models of such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) of the cytoplasmatic isoforms of the RNA-binding protein RBFOX1, and neuronal deletion of the small Ras GTPase DIRAS2. Maternal infections during pregnancy pose an increased risk for NPDs in the offspring. While viral-like MIA has been previously established elsewhere, this study was the first in our institution to implement the model. I validated NPD-relevant deficits in anxiety- and depression-like behaviours, as well as dose- and sex-specific social deficits in mouse offspring following MIA in early gestation. Proteomic analyses in embryonic and adult hippocampal (HPC) synaptoneurosomes highlighted novel and known targets affected by MIA. Analysis of the embryonic dataset implicated neurodevelopmental disruptions of the lipid, polysaccharide, and glycoprotein metabolism, important for proper membrane function, signalling, and myelination, for NPD-pertinent sequelae. In adulthood, the observed changes encompassed transmembrane trafficking and intracellular signalling, apoptosis, and cytoskeletal organisation pathways. Importantly, 50 proteins altered by MIA in embryonic and adult HPC were enriched in the NPD-relevant synaptic vesicle cycle. A persistently upregulated protein cluster formed a functional network involved in presynaptic signalling and proteins downregulated in embryos but upregulated in adults by MIA were correlated with observed social deficits. 49/50 genes encoding these proteins were significantly associated with NPD- and comorbidity-relevant traits in human phenome-wise association study data for psychiatric phenotypes. These findings highlight NPD-relevant targets for future study and early intervention in at-risk individuals. MIA-evoked changes in the neuroarchitecture of the NPD-relevant HPC and prefrontal cortex (PFC) of male and female mice highlighted sex- and region-specific alterations in dendritic and spine morphology, possibly underlining behavioural phenotypes. To further investigate genetic risk factors of NPDs, I performed a study based on the implications of RBFOX1’s pleiotropic role in neuropsychiatric disorders and previous preclinical findings. Cytoplasmatic OE of RBFOX1, which affects the stability and translation of thousands of targets, was used to disseminate its role in morphology and behaviour. RBFOX1 OE affected dendritic length and branching in the male PFC and led to spine alterations in both PFC and HPC. Due to previously observed ASD-like endophenotypes in our Rbfox1 KO mice and the importance of gene × environment effects on NPD susceptibility, I probed the interaction of cytoplasmatic OE and a low-dose MIA on offspring. Both RBFOX1 OE alone and with MIA led to increased offspring loss during the perinatal period. Preliminary data suggested that RBFOX1 OE × MIA might increase anxiety- and anhedonia-like behaviours. Morphological changes in the adult male OE HPC and PFC suggested increased spine density and reduced dendritic complexity. A small post-mortem study in human dorsolateral PFC of older adults did not reveal significant effects of a common risk variant on RBFOX1 abundance. To expand upon NPD genetic risks, I evaluated the effects of a homo- (KO) or heterozygous (HET) Diras2 deletion in a novel, neuron-specific mouse model. DIRAS2’s function is largely unknown, but it has been associated with ADHD in humans and neurodevelopment in vitro. In adult mice, there were subtle sex-specific effects on behaviour, i.e. more pronounced NPD-relevant deficits in males, in keeping with human data. KO mice had subtly improved cognitive performance, while HET mice exhibited behaviours in line with core ADHD symptoms, e.g. earning difficulties (females), response inhibition deficits and hyperactivity (males), suggesting Diras2 dose-sensitivity and sex-specificity. The morphological findings revealed multiple aberrations in dendritic and spine morphology in the adult PFC, HPC, and amygdala of HET males. KOs changes in spine and dendritic morphology were exclusively in the PFC and largely opposite to those in HETs and NPD-like phenotypes. Region- and genotype-specific expression changes in Diras2 and Diras1 were observed in six relevant brain regions of adult HET and KO females, also revealing differences in the survival and morphology regulator mTOR, which might underlie observed differences. In conclusion, the effects of MIA and partial Diras2 knockdown resembled each other in core, NPD-associated behavioural and morphological phenotypes, while cytoplasmatic RBFOX1 OE and full Diras2 KO differed from those. My findings suggest complex dose- and sex-dependent relationships between these prenatal and genetic interventions, whose NPD-relevant influences might converge onto neurodevelopmental molecular pathways. An assessment of such putative overlap, based on available data from the MIA proteomic analyses of embryonic and adult HPC, suggested the three models might be linked via downstream targets, interactions, and upstream regulators. Future studies should disseminate both distinct and shared aspects of MIA, RBFOX1, and DIRAS2 relevant to NPDs and build upon these findings.

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Section: Domain Modelmentioning

confidence: 99%

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Yotova

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Current Translational Medicine Approach in Schizophrenia: MicroRNA Research

Gümüş,

Bağcı,

Boztepe

et al. 2024

Psikiyatride Güncel Yaklaşımlar

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Schizophrenia is a common and complex psychiatric disorder with symptoms that significantly affect public health. Candidate gene studies reported that variants in genes involved in molecular processes associated with schizophrenia such as glutamatergic, dopaminergic, and GABAergic signaling pathways increase the risk of schizophrenia. Yet, the data obtained so far are incomplete for the development of new translational medicine approaches. Although the current research has promising results, it is still insufficient for the development of early diagnosis and treatment methods for schizophrenia management. Recent studies have reported that microRNAs detected in brain tissue and body fluids are differentially expressed in schizophrenia patients and control groups may be related to the etiology of schizophrenia. Although the determination of microRNA profiles associated with schizophrenia pathophysiology is very important for the development of new molecular approaches in the early diagnosis and treatment of the disease, the literature is still lacking in this field. Studies reporting schizophrenia-associated microRNAs in the existing literature have some limitations and methodological differences. In this review, we extracted the studies investigating the relationship between schizophrenia and microRNA in the last ten years and it was revealed that sample selection and microRNA detection methods are very important in terms of obtaining consistent results. Non-invasive detection of microRNAs expressed in the brain may have promising results for schizophrenia management. In this context, after a comprehensive literature search, miR-124-3p, miR-16-5p, and miR-34a-5p, which are differentially expressed in schizophrenia patients in the brain and blood, were prioritized as potential epigenetic biomarkers for schizophrenia. Our study provides data that can be utilized for translational medicine approaches to alleviate the burden of the disease in the community.

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Association between polymorphism rs2421943 of the insulin‐degrading enzyme and schizophrenia: Preliminary report

Cited by 2 publications

References 48 publications

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Current Translational Medicine Approach in Schizophrenia: MicroRNA Research

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