Gene Expression in Patient-Derived Neural Progenitors Implicates WNT5A Signaling in the Etiology of Schizophrenia

Evgrafov, Oleg V.; Armoskus, Chris; Wrobel, Bozena; Spitsyna, Valeria N.; Souaiaia, Tade; Herstein, Jennifer; Walker, Christopher; Nguyen, Joseph; Camarena, Adrian; Weitz, Jonathan; Kim, Jae Mun; Duarte, Edder Lopez; Wang, Kai; Simpson, George M.; Sobell, Janet L.; Medeiros, Helena; Pato, Michele T.; Pato, Carlos N.; Knowles, James A.

doi:10.1016/j.biopsych.2020.01.005

Cited by 30 publications

(33 citation statements)

References 80 publications

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“…To explore possible common mediators stemming from the epidemiological data, we took a hypothesis-driven, candidate molecular approach by using both patient-derived neuronal cells and animal models. Olfactory neuronal cells obtained through nasal biopsy from living patients and healthy subjects are expected to reflect molecular signatures of “pathophysiology”, a converged outcome of genetic and environmental interactions as well as associated stressors [18, 19, 32]. Accordingly, we suggest that alteration of insulin/IRS2 signaling underlies, at least in part, both major mental illnesses and diabetes, likely mediating their shared pathophysiology.…”

Section: Discussionmentioning

confidence: 94%

“…Olfactory neuronal cells may be a good surrogate tissue to capture neuronal molecular/biological changes associated with disease “pathophysiology”, because these cells are directly used after biopsy from patients and healthy controls without any genetic manipulation or reprogramming [18-20, 30-32]. Olfactory neuronal cells are prepared near to homogeneity [19] and expected to reflect molecular signatures of “pathophysiology”, a converged outcome of genetic and environmental interactions as well as associated stressors [18, 19, 32]. These cells are different from iPS cells from which we expect disease- and individual-associated trait changes (e.g., genetic impacts) related to the disease “pathogenesis” on cellular phenotypes.…”

Section: Resultsmentioning

confidence: 99%

“…First, we used the RNA-seq expression profile dataset provided by PsychENCODE [18, 31]. In the study, 36 genes were underscored as differentially expressed (FDR < 0.05) between SZ patients and healthy controls.…”

Section: Resultsmentioning

confidence: 99%

“…We conducted literature mining of the genes that were differentially expressed between SZ patients and healthy controls (FDR < 0.05) in olfactory neuronal cells in the PsychENCODE dataset [18]. Genes were annotated either insulin-related or -unrelated based on the criteria that more than 100 publications mentioned its gene symbol and insulin at the same time in the title or abstract in PubMed publications.…”

Section: Methodsmentioning

confidence: 99%

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From population to neuron: exploring common mediators for metabolic problems and mental illnesses

Takayanagi

Ishizuka

Laursen

et al. 2020

Preprint

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Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of "from population to neuron", combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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From population to neuron: exploring common mediators for metabolic problems and mental illnesses

Takayanagi

Ishizuka

Laursen

et al. 2020

Preprint

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“…To address this specific question, we conducted an unbiased molecular expression study on biopsied neuronal cells from the OE together with a volumetric assessment of the OB by using 3 Tesla magnetic resonance imaging (MRI) data from the same set of FEP patients and healthy controls. The biopsied neuronal cells (olfactory neuronal cells, ONCs) were used as molecular surrogates of neuronal cells, in particular those for stem cells and immature neuronal cells (Evgrafov et al, 2020; Horiuchi et al, 2013; Kano et al, 2013; Lavoie et al, 2017; Takayanagi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Volumetric alteration of olfactory bulb and immune-related molecular changes in olfactory epithelium in first episode psychosis patients

Yang

Hua

Etyemez

et al. 2021

Preprint

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BackgroundOlfactory dysfunction has been reproducibly reported in patients with psychosis, including first episode psychosis (FEP) patients. Consistently, structural abnormalities in the olfactory bulb (OB), a key region of the peripheral olfactory system, have also been reported in psychotic disorders. Meanwhile, air pollution and viral infections in the upper respiratory tract, including those of SARS-CoV-2, are reportedly risk factors for brain dysfunction and mental disorders. These risk factors can disturb the olfactory epithelium (OE) that is located adjacent to the OB and connected via direct neuronal projections. Nevertheless, it is unknown how a disturbance of the OE possibly affects the OB in the pathophysiological context of psychotic disorders.MethodsWe examined the volume of the OB in FEP patients and healthy controls from 3 Tesla magnetic resonance imaging and molecular expression profiles of olfactory neuronal cells (ONCs) enriched from freshly biopsied OE.ResultsWe observed a reduction of the OB volume in FEP patients compared with healthy controls. We also observed a significant alteration in gene expression profiles in the ONCs from FEP patients, supporting the pathological changes in the OE. Among such molecular changes, immune-related molecules and pathways were underscored in association with the OB volume changes in FEP patients.ConclusionsOur data support the OB and OE pathologies in FEP patients. Immune-related molecular changes in the OE can biologically link adverse factors in the nasal cavity, such as air pollution and viral infection, with the OB structural change, both of which have been reported for psychotic disorders.

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The Influence of Genotype on Phenotype in Contemporary Research into the Genetic Causes of Schizophrenia

Голимбет

Kostyuk

2022

Neurosci Behav Physi

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Gene Expression in Patient-Derived Neural Progenitors Implicates WNT5A Signaling in the Etiology of Schizophrenia

Cited by 30 publications

References 80 publications

From population to neuron: exploring common mediators for metabolic problems and mental illnesses

From population to neuron: exploring common mediators for metabolic problems and mental illnesses

Volumetric alteration of olfactory bulb and immune-related molecular changes in olfactory epithelium in first episode psychosis patients

The Influence of Genotype on Phenotype in Contemporary Research into the Genetic Causes of Schizophrenia

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