Showing papers by "Takeo Yoshikawa published in 2021"

Lipid Pathology of the Corpus Callosum in Schizophrenia and the Potential Role of Abnormal Gene Regulatory Networks with Reduced Microglial Marker Expression

Abstract: Structural changes in the corpus callosum have been reported in schizophrenia; however, the underlying molecular mechanism remains unclear. As the corpus callosum is high in lipid content, we analyzed the lipid contents of the corpora callosa from 15 patients with schizophrenia and 15 age- and sex-matched controls using liquid chromatography coupled to tandem mass spectrometry and identified lipid combinations associated with schizophrenia. Real-time quantitative polymerase chain reaction analyses using extended samples (schizophrenia, n = 95; control, n = 91) showed low expression levels of lipid metabolism-related genes and their potential upstream transcription factors in schizophrenia. Subsequent pathway analysis identified a gene regulatory network where nuclear factor of activated T cells 2 (NFATC2) is placed most upstream. We also observed low gene expression levels of microglial markers, inflammatory cytokines, and colony-stimulating factor 1 receptor (CSF1R), which is known to regulate the density of microglia, in the corpus callosum in schizophrenia. The interactions between CSF1R and several genes in the presently identified gene network originating from NFATC2 have been reported. Collectively, this study provides evidence regarding lipid abnormalities in the corpora callosa of patients with schizophrenia and proposes the potential role of impaired "NFATC2-relevant gene network-microglial axis" as its underlying mechanism.

Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons

Abstract: Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.

Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia

Abstract: We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.

Genetic risks of schizophrenia identified in a matched case–control study

Abstract: It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06–1.45, p < 0.001) for rs4680, 1.73 (95% CI 1.47–2.02, p < 0.0001) for rs1800497, and 1.79 (95% CI 1.35–2.36, p < 0.0001) for rs10770141. A significant relationship was also revealed among these three polymorphisms and schizophrenia, with corresponding coefficients (p < 0.0001). In this study, we also present a new scoring model for the identification of individuals with the disease risks. Using the cut-off value of 2, our model exhibited sensitivity for almost two-thirds of all of the schizophrenia patients: odds ratio 1.87, 95% CI 1.59–2.19, p < 0.0001. In conclusion, we identified significant associations of dopamine-related genetic combinations with schizophrenia. These findings suggest that some types of dopaminergic neurotransmission play important roles for development of schizophrenia, and this type of approach may also be applicable for other multifactorial diseases, providing a potent new risk predictor.