Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome
Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome
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DOI：
10.1212/01.wnl.0000123251.60485.ac
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发表时间：
2004-05-11
期刊：
影响因子：
9.9
通讯作者：
Allen, RP
中科院分区：
文献类型：
--
作者：
Connor, JR;Wang, XS;Allen, RP
背景：不宁腿综合症 (RLS) 是一种感觉运动障碍，影响 5% 至 10% 的人口。其病因尚不清楚，但 MRI 分析和尸检组织的免疫组织化学研究表明，RLS 患者的黑质 (SN) 铁含量低于正常水平。方法：通过激光捕获显微切割从四个 RLS 和四个对照大脑的 SN 中分离神经黑色素细胞，并通过免疫印迹分析获得铁管理蛋白表达谱。对细胞匀浆进行铁调节蛋白活性的结合测定。结果：与对照组相比，RLS 神经黑色素细胞中的铁蛋白、二价金属转运蛋白 1、铁转运蛋白和转铁蛋白受体 (TfR) 均减少。 RLS 神经黑色素细胞中的转铁蛋白增加。 RLS 神经黑色素细胞中的这种蛋白质谱与缺铁一致，但 TfR 表达减少而不是增加。分析铁调节蛋白（IRP1 和 IRP2）的浓度和活性，以确定 TfR 表达的转录后调节机制是否存在功能缺陷。 RLS 中总 IRP 活性、IRP1 活性和 IRP1 蛋白水平降低，但 RLS 中总 IRP2 蛋白水平未降低。结论：不宁腿综合征可能是由于神经黑色素细胞中铁调节蛋白 1 的缺陷导致转铁蛋白受体 mRNA 不稳定，导致细胞缺铁。
Background: Restless legs syndrome (RLS) is a sensory-movement disorder affecting 5 to 10% of the population. Its etiology is unknown, but MRI analyses and immunohistochemical studies on autopsy tissue suggest the substantia nigra (SN) of patients with RLS has subnormal amounts of iron. Methods: Neuromelanin cells from the SN of four RLS and four control brains were isolated by laser capture microdissection, and a profile of iron-management protein expression was obtained by immunoblot analysis. Binding assays for iron regulatory protein activity were performed on cell homogenates. Results: Ferritin, divalent metal transporter 1, ferroportin, and transferrin receptor (TfR) were decreased in RLS neuromelanin cells compared with control. Transferrin was increased in RLS neuromelanin cells. This protein profile in RLS neuromelanin cells is consistent with iron deficiency with the exception that TfR expression was decreased rather than increased. The concentration and activity of the iron regulatory proteins (IRP1 and IRP2) were analyzed to determine whether there was a functional deficit in the post-transcriptional regulatory mechanism for TfR expression. Total IRP activity, IRP1 activity, and IRP1 protein levels were decreased in RLS, but total IRP2 protein levels were not decreased in RLS. Conclusion: Restless legs syndrome may result from a defect in iron regulatory protein 1 in neuromelanin cells that promotes destabilization of the transferrin receptor mRNA, leading to cellular iron deficiency.