Neuroscience Institute, The Pennsylvania State University, University Park, PA, USA.
Neuroscience. 2013 Nov 12;252:13-23. doi: 10.1016/j.neuroscience.2013.07.058. Epub 2013 Aug 1.
A clear link exists between iron deficiency (ID) and nigrostriatal dopamine malfunction. This link appears to play an important role in at least restless legs syndrome (RLS) if not several other neurological diseases. Yet, the underlying mechanisms remain unclear. The effects of ID on gene expression in the brain have not been studied extensively. Here, to better understand how exactly ID alters dopamine functioning, we investigated the effects of ID on gene expression in the brain, seeking to identify any potential transcription-based mechanisms. We used six strains of recombinant inbred mice (BXD type) known to differ in susceptibility to ID in the brain. Upon weaning, we subjected mice from each strain to either an iron-deficient or iron-adequate diet. After 100 days of dietary treatment, we measured the effects of ID on gene expression in the ventral midbrain, a region containing the substantia nigra. The substantia nigra is the base of the nigrostriatal dopamine pathway and a region particularly affected by iron loss in RLS. We screened for ID-induced changes in expression, including changes in that of both iron-regulating and dopamine-related genes. Results revealed a number of expression changes occurring in ID, with large strain-dependent differences in the genes involved and number of expression changes occurring. In terms of dopamine-related genes, results revealed ID-induced expression changes in three genes with direct ties to nigrostriatal dopamine functioning, two of which have never before been implicated in an iron-dopamine pathway. These were stromal cell-derived factor 1 (Cxcl12, or SDF-1), a ferritin regulator and potent dopamine neuromodulator, and hemoglobin, beta adult chain 1 (Hbb-b1), a gene recently shown to play a functional role in dopaminergic neurons. The extent of up-regulation of these genes varied by strain. This work not only demonstrates a wide genetic variation in the transcriptional response to ID in the brain, but also reveals two novel biochemical pathways by which iron may potentially alter dopamine function.
缺铁（ID）与黑质纹状体多巴胺功能障碍之间存在明确的联系。这种联系似乎在至少不宁腿综合征（RLS）中起重要作用，如果不是在其他几种神经疾病中也是如此。然而，其潜在机制尚不清楚。ID 对大脑中基因表达的影响尚未得到广泛研究。在这里，为了更好地了解 ID 如何确切改变多巴胺功能，我们研究了 ID 对大脑中基因表达的影响，试图确定任何潜在的基于转录的机制。我们使用了六种已知对大脑中 ID 易感性不同的重组近交系（BXD 型）小鼠。断奶后，我们将来自每种品系的小鼠分别置于缺铁或铁充足的饮食中。经过 100 天的饮食处理后，我们测量了 ID 对腹侧中脑（包含黑质的区域）基因表达的影响。黑质是黑质纹状体多巴胺通路的基础，也是 RLS 中铁丢失特别影响的区域。我们筛选了 ID 诱导的表达变化，包括铁调节和多巴胺相关基因的表达变化。结果显示，在 ID 中发生了许多表达变化，涉及的基因及其表达变化的数量存在很大的品系依赖性差异。就多巴胺相关基因而言，结果显示有三个与黑质纹状体多巴胺功能直接相关的基因发生了 ID 诱导的表达变化，其中两个以前从未涉及铁-多巴胺途径。这是基质细胞衍生因子 1（Cxcl12，或 SDF-1），一种铁蛋白调节剂和强大的多巴胺神经调节剂，以及血红蛋白，β成人链 1（Hbb-b1），一个最近被证明在多巴胺能神经元中发挥功能作用的基因。这些基因的上调程度因品系而异。这项工作不仅证明了大脑对 ID 的转录反应存在广泛的遗传变异，还揭示了铁可能潜在改变多巴胺功能的两种新的生化途径。
