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首页> 外文学位 >Disordered iron regulation in manganese Parkinsonism: Roles of divalent metal transporter 1, metal transporter protein 1 and transferrin receptor in the blood-CSF barrier.
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Disordered iron regulation in manganese Parkinsonism: Roles of divalent metal transporter 1, metal transporter protein 1 and transferrin receptor in the blood-CSF barrier.

机译：锰帕金森病中的铁调节紊乱：血脑脊液屏障中二价金属转运蛋白1，金属转运蛋白1和转铁蛋白受体的作用。

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摘要

Overexposure to manganese (Mn) is believed to be one of the environmental factors that causes neurological symptoms resembling Parkinson's disease, referred to as manganism. For a chemical to induce brain dysfunction, it must pass across brain barriers. The barrier that restricts substance movement between the blood circulation and the cerebrospinal fluid (CSF) is termed the blood-CSF barrier (BCB), which primarily resides in the choroid plexus (CP). Previous studies have demonstrated that Mn exposure, decreases iron (Fe) levels in the blood and increases Fe concentrations in the CSF. This indicates a compartmental shift of Fe between the blood and CSF. Fe homeostasis is regulated by three major Fe transporters, i.e., divalent metal transporter 1 (DMT1), metal transporter protein 1 (MTP1), and transferrin receptor (TfR). We hypothesized that Mn exposure alters the expression, subcellular location, and function of DMT1, MTP1 and TfR at the BCB in the CP, which contributes to disordered Fe homeostasis in Mn-induced Parkinsonism. This project (i) demonstrated that Mn exposure increased the expression of OMT1 in the CP at both mRNA and protein levels as a result of increased binding between the IRE-containing DMT1 mRNA and the iron regulatory proteins, (ii) characterized the subcellular location of DMT1, MTP1 and TfR in the CP by confocal microscopy and identified that Mn/Fe exposure from the CSF caused intracellular trafficking of MTP1 and TfR, (iii) found that MTP1 dissociated from endoplasmic reticulum following Mn exposure in the choroidal epithelial Z310 cells as determined by use of GFP-tagged proteins and DMT1 was cytosolically localized, (iv) identified that transferrin-bound Fe favored influx from the blood to the CSF through the use of a bicameral Transwell device, while Mn exposure greatly increased free Fe transport favored in the opposite direction, and (v) discovered a lower Fe clearance in the CSF of Mn-treated rats by a ventriculocisternal brain perfusion technique. Overall, we conclude that Mn exposure alters the expression and subcellular location of these metal transporters (DMT1, MTP1 and TfR) in the BCB, leading to an increased Fe level in the CSF. It is concluded that these changes underlie Mn-elicited Parkinsonism.
机译：过度暴露于锰（Mn）被认为是导致类似于帕金森氏病（称为锰症）的神经系统症状的环境因素之一。为了使化学物质诱发脑功能障碍，它必须穿过脑屏障。限制物质在血液循环和脑脊液（CSF）之间运动的屏障被称为血CSF屏障（BCB），主要位于脉络丛（CP）中。先前的研究表明，锰暴露会降低血液中的铁（Fe）水平，并会增加CSF中的Fe浓度。这表明铁在血液和脑脊液之间的间隔转移。铁稳态由三种主要的铁转运蛋白，即二价金属转运蛋白1（DMT1），金属转运蛋白1（MTP1）和转铁蛋白受体（TfR）调节。我们假设Mn暴露会改变CP中BCB处DMT1，MTP1和TfR的表达，亚细胞位置和功能，这会导致Mn诱发的帕金森病中铁稳态的紊乱。该项目（i）表明，由于含IRE的DMT1 mRNA与铁调节蛋白之间的结合增加，锰暴露增加了CP在mRNA和蛋白水平上OMT1的表达。通过共聚焦显微镜检查CP中的DMT1，MTP1和TfR，并确定从CSF暴露的Mn / Fe引起MTP1和TfR的细胞内运输。（iii）发现，在脉络膜上皮Z310细胞中Mn暴露后，MTP1从内质网解离。通过使用GFP标记的蛋白和DMT1进行了细胞溶胶定位，（iv）确定了运铁蛋白结合的Fe通过使用双室Transwell装置促进了从血液向CSF的流入，而Mn暴露极大地增加了Fe的自由铁转运。 （v）通过脑室胸骨后脑灌注技术发现了Mn处理的大鼠的CSF中较低的Fe清除率。总的来说，我们得出结论，锰暴露会改变这些金属转运蛋白（DMT1，MTP1和TfR）在BCB中的表达和亚细胞位置，从而导致CSF中的Fe水平升高。结论是这些变化是锰引起的帕金森氏症的基础。

著录项

  • 作者

    Wang, Xueqian.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Biology Neuroscience.; Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 203 p.
  • 总页数 203
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;毒物学（毒理学）;
  • 关键词

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