Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.
Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.
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DOI：
10.1001/archgenpsychiatry.2011.71
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发表时间：
2011-07
影响因子：
--
通讯作者：
Schwarcz, Robert
中科院分区：
文献类型：
--
作者：
Wonodi, Ikwunga;Stine, O. Colin;Sathyasaikumar, Korrapati V.;Roberts, Rosalinda C.;Mitchell, Braxton D.;Hong, L. Elliot;Kajii, Yasushi;Thaker, Gunvant K.;Schwarcz, Robert
犬尿烯酸是色氨酸降解的犬尿氨酸途径的代谢产物，是N-甲基-d-天冬氨酸和α7烟碱乙酰胆碱受体的拮抗剂，并调节谷氨酸、多巴胺和乙酰胆碱信号传导。精神分裂症患者脑和脑脊液中皮质犬尿烯酸浓度升高。近端原因可能是犬尿氨酸3-单加氧酶（KMO）受损，KMO是犬尿氨酸途径分支点的限速酶。检测精神分裂症患者和健康对照者的额眼区（FEF; Brodmann area 6）死后组织中KMO信使RNA表达和KMO酶活性，探讨KMO单核苷酸多态性与精神分裂症眼内表型的关系。病例对照尸检和临床研究。马里兰州脑科学研究中心门诊部尸检标本来自精神分裂症患者（n=32）和对照供体（n=32）以及精神分裂症患者（n=248）和健康对照（n=228）的临床样本。比较精神分裂症患者和对照者死后FEF组织中定量KMO信使RNA表达和KMO酶活性，以及KMO单核苷酸多态性与死后FEF和精神分裂症及眼内表型（即，平稳追踪眼球运动和眼内延迟反应）信使RNA表达的相关性。在死后组织中，我们发现精神分裂症患者FEF中KMO基因表达和KMO酶活性显著降低。在临床样本中，KMO rs 2275163与精神分裂症的诊断无关，但对预测追踪和视觉空间工作记忆内表型有适度的影响。我们的研究结果提供了会聚线的证据，暗示减少KMO活动的精神分裂症和相关的神经认知缺陷的发病病理生理学。
Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway. To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes. Case-control postmortem and clinical study. Maryland Brain Collection, outpatient clinics. Postmortem specimens from schizophrenia patients (n=32) and control donors (n=32) and a clinical sample of schizophrenia patients (n=248) and healthy controls (n=228). Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response). In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes. Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.
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影响因子：
10.6
作者：
Erhardt, S;Schwieler, L;Geyer, M
通讯作者：
Geyer, M
影响因子：
2.5
作者：
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影响因子：
6.6
作者：
Braff, David L.;Freedman, Robert;Gottesman, Irving I.
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影响因子：
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作者：
Avila, MT;Adami, HM;Thaker, GK
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Mirbase：MicroRNA基因组学的工具。
影响因子：
14.9
作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.