• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia.
【24h】

Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia.

机译：人神经元细胞和大脑皮层中钴胺素状态的氧化还原调节：对衰老，自闭症和精神分裂症的影响。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Cobalamin (Cbl), also known as vitamin B12, is an essential micronutrient which mammals must acquire through diet. It is a critical cofactor for two metabolic reactions in its active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). MeCbl is the cofactor for folate-dependent methylation of homocysteine (HCY) to methionine by methionine synthase (MS) in the cytoplasm, and AdoCbl is the cofactor for conversion of methylmalonylCoA to succinylCoA by methylmalonyl CoA mutase (MCM) in mitochondria. Since MS activity determines the ratio of the methyl donor S-adenosylmethionine (SAM) to the endogenous methylation inhibitor S-adenosylhomocysteine (SAH), MeCbl is poised to influence hundreds of SAM-dependent methylation reactions, affecting nearly every aspect of metabolism. Important among these reactions is methylation of DNA and histones, which combine to exert dynamic epigenetic control over gene expression and plays a crucial role in brain development.;Neurologic dysfunction is a primary clinical manifestation of Cbl deficiency and cerebral sequelae of Cbl deficiency include impaired cognition and memory, as well as mood disorders. The structure of Cbl contains a corrin ring and at the center of the ring is a cobalt atom which can be linked to different ligands in the upper beta-axial position, giving rise to different Cbl species. By developing a novel HPLC/electrochemical detection-based assay, I measured the levels of six different naturally occurring Cbl species including AdoCbl and MeCbl, in postmortem human frontal cortex of control subjects, from 19 weeks of fetal development through 80 years of age, and subjects with autism or schizophrenia. Results showed that levels of total Cbl and active Cbl species were significantly decreased in older control subjects (>60 yrs of age) as well as in autistic and schizophrenic subjects.;Oxidative stress as indicated by low level of primary cellular antioxidant glutathione (GSH) has been highlighted in aging and neurological disorders including autism and schizophrenia. Cbl deficiency can be caused by dietary insufficiency, malabsorption or defective intracellular Cbl processing, all of which eventually lead to inadequate of synthesis of metabolically active Cbl species. Using both the SH-SY5Y human neuroblastoma cell line as a neuronal cell model and a knock-out mouse model with low GSH level, my results revealed that neuronal Cbl metabolism was redox-dependent and oxidative stress impaired the cellular Cbl uptake and the formation of active Cbl species from inactive species, suggesting that oxidative stress may lead to the dramatic reduction of Cbl previously identified in aging, autism and schizophrenia.;Neuregulin-1 (NRG-1) is an epidermal growth factor (EGF)-like growth factor that plays critical roles in development of the central nervous system, as well as maintaining its normal function. Decreased levels of NRG-1 and its receptor ErbB4 are observed in prefrontal cortex of patients with schizophrenia and the NRG-1 gene has been identified as a leading susceptibility locus for schizophrenia. NRG-1 treatment of SH-SY5Y cells in my studies showed that NRG-1 stimulated neuronal synthesis of AdoCbl and MeCbl by both promoting conversion of inactive to active Cbl species and increasing neuronal Cbl uptake. Further studies revealed that NRG-1 achieved these effects by stimulating excitatory amino acid transporter-3 (EAAT3)-mediated cysteine uptake and cysteine-dependent GSH synthesis.;Since the brain is present in a unique redox environment and both selenium-containing selenoproteins and GSH play important roles in the brain redox system, the effects of GSH-biased and selenium-biased redox conditions on neuronal cobalamin metabolism have also been investigated. Results showed that cellular Cbl uptake was impaired under oxidative stress conditions and synthesis of active Cbl species was impaired when extracellular cysteine and selenium were scarce.;These findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect adaptation to increasing antioxidant demand, while accelerated deficits may contribute to neurodevelopmental and neuropsychiatric disorders. In vitro and in vivo studies not only identify novel neuroprotective roles for NRG-1 in terms of stimulating antioxidant and Cbl synthesis, but also reveal the role of cellular redox status in regulating Cbl metabolism and its related pathways. Overall, this thesis addresses the role of Cbl in brain function and neurological disorders, identifies the underlying regulatory mechanism of brain Cbl metabolism and provides a potential mechanistic link between Cbl deficiency and neurological disorders. Together these results may aid in the improvement of our understanding about the neurological role of Cbl.
机译：钴胺素（Cbl），也称为维生素B12，是哺乳动物必须通过饮食获得的必需微量营养素。它是两种代谢形式的活性代谢的关键辅因子，甲基钴胺素（MeCbl）和腺苷钴胺素（AdoCbl）。 MeCbl是在细胞质中通过蛋氨酸合酶（MS）将高半胱氨酸（HCY）转化为蛋氨酸的叶酸依赖性甲基化的辅因子，而AdoCbl是通过线粒体中的甲基丙二酰辅酶A突变酶（MCM）将甲基丙二酰辅酶A转化为琥珀酰辅酶A的辅因子。由于MS活性决定了甲基供体S-腺苷甲硫氨酸（SAM）与内源性甲基化抑制剂S-腺苷同型半胱氨酸（SAH）的比例，因此MeCbl有望影响数百种SAM依赖性甲基化反应，几乎影响代谢的各个方面。在这些反应中，重要的是DNA和组蛋白的甲基化，二者结合起来对基因表达进行动态表观遗传控制，并在大脑发育中起关键作用。；神经系统功能障碍是Cbl缺乏的主要临床表现，Cbl缺乏的脑后遗症包括认知障碍。和记忆力以及情绪障碍。 Cbl的结构包含一个柯林环，并且在环的中心是一个钴原子，该钴原子可以在较高的β轴位置与不同的配体连接，从而产生不同的Cbl物种。通过开发一种新颖的基于HPLC /电化学检测的分析方法，我测量了从19周胎儿发育到80岁的人的死后额叶皮层中六种不同的天然Cbl物种的水平，包括AdoCbl和MeCbl。自闭症或精神分裂症患者。结果表明，在年龄较大的对照受试者（> 60岁）以及自闭症和精神分裂症受试者中，总Cbl和活性Cbl种类的水平显着降低。氧化应激表现为低水平的原代细胞抗氧化剂谷胱甘肽（GSH）在衰老和神经系统疾病（包括自闭症和精神分裂症）中已被强调。 Cbl缺乏症可能是由于饮食不足，吸收不良或细胞内Cbl加工不良而引起的，所有这些最终导致代谢活性Cbl物种合成不足。使用SH-SY5Y人成神经细胞瘤细胞系作为神经元细胞模型和低谷胱甘肽水平的基因敲除小鼠模型，我的结果表明神经元Cbl代谢是氧化还原依赖性的，氧化应激会损害细胞对Cbl的摄取和形成。活跃的Cbl物种来自非活跃的物种，这表明氧化应激可能导致先前在衰老，自闭症和精神分裂症中发现的Cbl急剧降低.Neuregulin-1（NRG-1）是一种表皮生长因子（EGF）样的生长因子，在中枢神经系统的发育以及维持其正常功能中起关键作用。在精神分裂症患者的前额叶皮层中观察到NRG-1及其受体ErbB4的水平降低，并且NRG-1基因已被确定为精神分裂症的主要易感基因座。在我的研究中，NRG-1对SH-SY5Y细胞的处理表明NRG-1可以通过促进非活性Cbl物种向活性Cbl物种的转化并增加神经元Cbl的摄取来刺激AdoCbl和MeCbl的神经元合成。进一步的研究表明，NRG-1通过刺激兴奋性氨基酸转运蛋白3（EAAT3）介导的半胱氨酸摄取和半胱氨酸依赖性GSH合成而实现了这些作用。由于大脑存在于独特的氧化还原环境中，并且含硒的硒蛋白和GSH在脑氧化还原系统中起重要作用，还研究了GSH偏和硒偏氧化还原条件对神经元钴胺素代谢的影响。结果表明，当细胞外半胱氨酸和硒缺乏时，在氧化应激条件下细胞Cbl的摄取会受到损害，活性Cbl物质的合成也受到损害;这些发现表明，在整个生命周期中，大脑维生素B12的状态以前未被认识到的下降可能反映了对增加的适应抗氧化剂的需求，同时加速的赤字可能导致神经发育和神经精神疾病。体外和体内研究不仅在刺激抗​​氧化剂和Cbl合成方面确定了NRG-1的新型神经保护作用，而且还揭示了细胞氧化还原状态在调节Cbl代谢及其相关途径中的作用。总体而言，本文探讨了Cbl在脑功能和神经系统疾病中的作用，确定了脑Cbl代谢的潜在调控机制，并提供了Cbl缺乏与神经系统疾病之间的潜在机制联系。这些结果加在一起可能有助于改善我们对Cbl神经功能的理解。

著录项

  • 作者

    Zhang, Yiting.;

  • 作者单位

    Northeastern University.;

  • 授予单位 Northeastern University.;
  • 学科 Pharmaceutical sciences.;Pharmacology.;Aging.;Psychobiology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 153 p.
  • 总页数 153
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号