Choroid Plexus a Target in Metal-Induced Neurotoxicity

脉络丛是金属引起的神经毒性的目标

• 批准号: 6830697
• 负责人: WEI ZHENG
• 金额: $ 30.27万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830697
• 关键词: Parkinson' s disease; biological transport; cell migration; cerebrospinal fluid; choroid plexus; environmental toxicology; ferritin; iron metabolism; laboratory rat; manganese; metal poisoning; neurotoxicology; neurotoxins; protein degradation; receptor expression; transferrin; transferrin receptor

DESCRIPTION (provided by applicant): The recent addition of a manganese (Mn)-containing antiknock compound methylcyclo-pentadienyl Mn tricarbonyl (MMT) to the US gasoline supply has raised a great concern about the health risks associated with a potential increase in the environmental levels of Mn. Both environmental and occupational exposures to (Mn) result in neurodegenerative symptoms resembling Parkinson's disease. However, the mechanisms underlying Mn neurotoxicity remain unknown. Our recent results show that in vivo and in vitro exposures to Mn alter both systemic and subcellular Fe status. While the former facilitates influx of Fe from the blood circulation to the cerebral spinal fluid (CSF), the latter promotes cellular Fe overload. We also found that accumulation of Mn in the choroid plexus, a tissue where blood-CSF barrier resides, enhances the density of transferrin receptor (TfR) mRNA, which has 3' binding IRE (iron responsive element) loops receptive to [4Fe-4S] cluster-containing iron regulatory protein-1 (IRP-1, or cytosolic aconitase). These findings have led us to propose that the mechanism by which Mn causes abnormal Fe metabolism is likely via its interaction with IRP-1 and the subsequent overexpression of TfR. The events, in turn, expedite Fe transport at the brain barrier systems and aggravate Fe accumulation in neuronal cells. Thus, we hypothesize in this proposal that accumulation of Mn in the choroid plexus alters Fe regulatory mechanisms in the blood-CSF barrier and thereby disturbs Fe homeostasis in the CSF, which may contribute to Mn-induced neurodegenerative Parkinsonism. Our research goals are to better understand the mechanism of Mn-induced Parkinsonism and in so doing identify and prevent environmental causes of neurodegenerative diseases. Our specific aims are (1) to test the working hypothesis that Mn exposure alters the Fe regulatory mechanism in the choroid plexus, leading to a distorted Fe status in the CSF. We will define the dose and time response relationship of Mn exposure and Fe in CSF, blood, and choroid plexus, examine the activity of IRP-1, and determine the expression of TfR in blood-CSF barrier and selected brain areas; (2) to test the working hypothesis that Mn-facilitated transport of Fe at the blood-CSF barrier is directed toward the CSF and quantitatively is more significant than transport by the blood-brain barrier. We will use in vitro transport models to determine the direction and magnitude of Fe fluxes at two major brain barriers and to investigate if blocking of cellular trafficking of TfR antagonizes Mn-augmented unidirectional transport of Fe; and (3) to test the working hypothesis that alteration by Mn of cellular Fe regulation takes place at the level of mRNA expression, but not at the level of transcriptional modulation of genomic DNA. We will deterrnine the effect of Mn on RNA binding capability of IRP-1 and pertinent expression of TfR, examine if Mn inhibits degradation of TfR mRNA, and study cellular ferritin status in both barriers. In addition, we will study the effect of Mn on the RNA binding capability of a newly discovered IRP which regulates the synthesis of an [Fe-S] subunit of Complex-I.

描述（由申请人提供）：最近添加了锰 （MN） - 含有抗抗抗抗甲基甲基甲基苯基甲基苯基MN Tricarbonyl（MMT） 美国汽油供应对健康风险引起了极大的关注 与MN环境水平的潜在增加有关。两个都 环境和职业接触（MN）导致神经退行性 症状类似于帕金森氏病。但是，MN的基础机制 神经毒性仍然未知。我们最近的结果表明，体内和体外 暴露于MN会改变全身和亚细胞FE状态。而前者 促进Fe从血液循环到脑脊柱的涌入 流体（CSF），后者促进了细胞FE超负荷。我们还发现 Mn在脉络丛中的积累，该组织的血液-CSF屏障 居住，增强了具有3'的转铁蛋白受体（TFR）mRNA的密度 结合IRE（铁响应元件）环接收到[4FE-4S] 含簇的铁调节蛋白-1（IRP-1或胞质刺蛋白酶）。 这些发现使我们提出MN引起的机制 FE代谢异常可能是通过与IRP-1的相互作用和 随后的TFR过表达。反过来，这些事件加快了FE运输 脑屏障系统并加剧神经元细胞中的FE积累。 因此，我们在这一提议中假设MN在脉络膜中的积累 神经丛改变血液-CSF屏障中的FE调节机制，从而改变 在CSF中打扰了FE FE稳态，这可能有助于MN引起 神经退行性帕金森主义。我们的研究目标是更好地了解 MN引起的帕金森氏症机制，因此确实识别并防止 神经退行性疾病的环境原因。我们的具体目的是（1） 测试MN暴露会改变FE调节的工作假设 脉络丛的机理，导致CSF中的Fe状态扭曲。 我们将定义MN暴露和Fe的剂量和时间响应关系 CSF，血液和脉络丛，检查IRP-1的活性，并确定 TFR在血液-CSF屏障和选定的大脑区域中的表达； （2）至 测试MN转运Fe在该的工作假设 血液-CSF屏障针对CSF，而定量则更多 比血脑屏障的运输意义重大。我们将在体外使用 运输模型以确定两个处的Fe通量的方向和大小 主要的大脑障碍，并调查是否阻止细胞运输 TFR拮抗Mn的Fe的单向运输； （3）测试 工作假设，即Mn对细胞Fe调节的改变 位于mRNA表达水平，但不在转录水平 基因组DNA的调节。我们将威慑Mn对RNA结合的影响 IRP-1和TFR相关表达的能力，检查MN是否抑制 TFR mRNA的降解和两个屏障中的细胞铁蛋白状态。 此外，我们将研究MN对A的RNA结合能力的影响 新发现的IRP调节[Fe-s]亚基的合成 复合体-I。