Hagihara Hideo, Murano Tomoyuki, Miyakawa Tsuyoshi
Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan.
Front Psychiatry. 2023 May 2;14:1151480. doi: 10.3389/fpsyt.2023.1151480. eCollection 2023.
Hydrogen ion (H) is one of the most potent intrinsic neuromodulators in the brain in terms of concentration. Changes in H concentration, expressed as pH, are thought to be associated with various biological processes, such as gene expression, in the brain. Accumulating evidence suggests that decreased brain pH is a common feature of several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and Alzheimer's disease. However, it remains unclear whether gene expression patterns can be used as surrogates for pH changes in the brain. In this study, we performed meta-analyses using publicly available gene expression datasets to profile the expression patterns of pH-associated genes, whose expression levels were correlated with brain pH, in human patients and mouse models of major central nervous system (CNS) diseases, as well as in mouse cell-type datasets. Comprehensive analysis of 281 human datasets from 11 CNS disorders revealed that gene expression associated with decreased pH was over-represented in disorders including schizophrenia, bipolar disorder, autism spectrum disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, and brain tumors. Expression patterns of pH-associated genes in mouse models of neurodegenerative disease showed a common time course trend toward lower pH over time. Furthermore, cell type analysis identified astrocytes as the cell type with the most acidity-related gene expression, consistent with previous experimental measurements showing a lower intracellular pH in astrocytes than in neurons. These results suggest that the expression pattern of pH-associated genes may be a surrogate for the state- and trait-related changes in pH in brain cells. Altered expression of pH-associated genes may serve as a novel molecular mechanism for a more complete understanding of the transdiagnostic pathophysiology of neuropsychiatric and neurodegenerative disorders.
就浓度而言，氢离子（H⁺）是大脑中最有效的内源性神经调节剂之一。以pH值表示的H⁺浓度变化被认为与大脑中的各种生物过程相关，如基因表达。越来越多的证据表明，脑pH值降低是包括精神分裂症、双相情感障碍、自闭症谱系障碍和阿尔茨海默病在内的几种神经精神疾病的共同特征。然而，基因表达模式是否可作为大脑中pH值变化的替代指标仍不清楚。在本研究中，我们使用公开可用的基因表达数据集进行荟萃分析，以描绘pH值相关基因的表达模式，这些基因的表达水平与大脑pH值相关，存在于主要中枢神经系统（CNS）疾病的人类患者和小鼠模型以及小鼠细胞类型数据集中。对来自11种CNS疾病的281个人类数据集的综合分析表明，与pH值降低相关的基因表达在包括精神分裂症、双相情感障碍、自闭症谱系障碍、阿尔茨海默病、亨廷顿舞蹈病、帕金森病和脑肿瘤等疾病中过度表达。神经退行性疾病小鼠模型中pH值相关基因的表达模式显示出随着时间推移pH值降低的共同时间进程趋势。此外，细胞类型分析确定星形胶质细胞是与酸度相关基因表达最多的细胞类型，这与之前的实验测量结果一致，即星形胶质细胞的细胞内pH值低于神经元。这些结果表明，pH值相关基因的表达模式可能是脑细胞中与状态和特质相关的pH值变化的替代指标。pH值相关基因的表达改变可能作为一种新的分子机制，有助于更全面地理解神经精神和神经退行性疾病的跨诊断病理生理学。
