Diagnosis- and Cell Type-Specific Mitochondrial Functional Pathway Signatures in Schizophrenia and Bipolar Disorder.
Diagnosis- and Cell Type-Specific Mitochondrial Functional Pathway Signatures in Schizophrenia and Bipolar Disorder.
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DOI：
10.1176/appi.ajp.2020.19111210
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发表时间：
2020-12-01
期刊：
影响因子：
--
通讯作者：
Lewis DA
中科院分区：
文献类型：
--
作者：
Glausier JR;Enwright JF 3rd;Lewis DA
精神分裂症和双相情感障碍的共同危险因素和临床特征可能通过线粒体功能障碍联系在一起。然而，线粒体功能障碍的严重程度和/或受影响的特定线粒体功能通路在不同的诊断中可能不同，特别是在单个细胞类型的水平上。获得了精神分裂症或双相情感障碍受试者背外侧前额叶皮质(DLPFC)灰质以及第3层和第5层锥体神经元的线粒体功能通路基因集的转录图谱数据。采用双重策略进行分析：1)鉴定差异表达基因(Deg)及其功能途径丰富；2)应用加权基因共表达网络。这些分析在长期接触抗精神病药物的猴子身上重复，以确定它们对线粒体相关基因表达的影响。在DLPFC灰质，41%的线粒体相关基因在精神分裂症中差异表达，8%在双相情感障碍中差异表达。在精神分裂症患者中，83%的DEGS表现出较低的表达，并且这些表达在三条功能通路上显著丰富，每条通路都指示能量产生。双相情感障碍患者的DEG在功能途径上没有得到丰富。这种与疾病相关的发现模式也在锥体神经元中被发现。没有一个基因表达改变扰乱了共表达模块，DEG也不是抗精神病药物所致。精神分裂症和双相情感障碍在DLPFC中似乎没有相似的线粒体变化。精神分裂症能量产生基因的选择性和协同下调与锥体神经元放电的慢性减少的效应是一致的，这一活性的增强可能成为治疗的靶点。
The shared risk factors and clinical features in schizophrenia and bipolar disorder may be linked via mitochondrial dysfunction. However, the severity of mitochondrial dysfunction, and/or the specific mitochondrial functional pathways affected, might differ between diagnoses, especially at the level of individual cell types. Transcriptomic profiling data for a gene set indexing mitochondrial functional pathways were obtained for dorsolateral prefrontal cortex (DLPFC) gray matter and layer 3 and layer 5 pyramidal neurons of subjects with schizophrenia or bipolar disorder. Analyses were conducted using a dual strategy: 1) identification of differentially-expressed genes (DEGs) and their functional pathway enrichment, and 2) application of weighted gene co-expression network. These analyses were repeated in monkeys chronically exposed to antipsychotic drugs to determine their effect on mitochondrial-related gene expression. In DLPFC gray matter, 41% of mitochondrial-related genes were differentially-expressed in schizophrenia whereas 8% were differentially-expressed in bipolar disorder. In schizophrenia, 83% of DEGs showed lower expression, and these were significantly enriched for three functional pathways, each indexing energy production. DEGs in bipolar disorder were not enriched for functional pathways. This disease-related pattern of findings was also identified in pyramidal neurons. None of the gene expression alterations disrupted co-expression modules, and DEGs were not attributable to antipsychotic medications. Schizophrenia and bipolar disorder do not appear to share similar mitochondrial alterations in the DLPFC. The selective and coordinated down-regulation of energy production genes in schizophrenia is consistent with the effects of chronic reductions in pyramidal neuron firing, and enhancement of this activity may serve as a therapeutic target.
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影响因子：
7
作者：
Barshad G;Blumberg A;Cohen T;Mishmar D
通讯作者：
Mishmar D
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
DOI：
10.1523/jneurosci.0026-12.2012
发表时间：
2012-06-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hall CN;Klein-Flügge MC;Howarth C;Attwell D
通讯作者：
Attwell D
影响因子：
11
作者：
Arion, D.;Corradi, J. P.;Tang, S.;Datta, D.;Boothe, F.;He, A.;Cacace, A. M.;Zaczek, R.;Albright, C. F.;Tseng, G.;Lewis, D. A.
通讯作者：
Lewis, D. A.
影响因子：
10.6
作者：
Horvath, Szatmar;Mirnics, Karoly
通讯作者：
Mirnics, Karoly