BRAIN TRANSCRIPTOME PERTURBATIONS IN THE TRANSFERRIN RECEPTOR 2 MUTANT MOUSE SUPPORT THE CASE FOR BRAIN CHANGES IN IRON LOADING DISORDERS, INCLUDING EFFECTS RELATING TO LONG-TERM DEPRESSION AND LONG-TERM POTENTIATION
BRAIN TRANSCRIPTOME PERTURBATIONS IN THE TRANSFERRIN RECEPTOR 2 MUTANT MOUSE SUPPORT THE CASE FOR BRAIN CHANGES IN IRON LOADING DISORDERS, INCLUDING EFFECTS RELATING TO LONG-TERM DEPRESSION AND LONG-TERM POTENTIATION
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DOI：
10.1016/j.neuroscience.2013.01.014
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发表时间：
2013-04-03
期刊：
影响因子：
3.3
通讯作者：
Johnstone, D. M.
中科院分区：
文献类型：
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作者：
Acikyol, B.;Graham, R. M.;Johnstone, D. M.
脑内的铁异常与几种罕见但严重的神经退行性疾病有关。越来越多的证据表明，更常见的全身性铁负荷障碍，如血色病，也可能对大脑产生重要影响。为了确定不同形式的血色病的共同特征，我们使用微阵列和实时逆转录聚合酶链反应（RT-PCR）来评估转铁蛋白受体2突变小鼠（Tfr 2（mut））的脑转录组谱，相对于野生型对照小鼠，转铁蛋白受体2突变小鼠是一种罕见的遗传性血色病模型。结果与我们以前在饮食补充铁的野生型小鼠和Hfe（-/-）小鼠（一种常见类型的遗传性血色病模型）中的发现进行了比较。对于在所有三种模型中相对于对照显示显著变化的转录物，存在完美的（100%）方向一致性（即，转录物在所有模型中增加或在所有模型中减少）。遗传性血色素沉着症的两种模型的比较显示出比膳食铁补充小鼠更明显的变化，揭示了许多共同的分子效应。通路分析强调了与长期抑制（6.8倍富集，p = 5.4 x 10（-7））和在较小程度上与长期增强（3.7倍富集，p = 0.01）相关的基因的变化，这些通路的关键基因的转录普遍减少，这些基因参与调节突触强度和功效，对记忆和学习至关重要。这些模型之间的一致性表明，这些发现是可靠的，并加强了以前的证据，即铁负荷障碍会影响大脑。脑现象的扰动，如长时程抑郁和长时程增强，可能部分解释了一些血色素沉着症患者的神经系统症状。(c)2013年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Iron abnormalities within the brain are associated with several rare but severe neurodegenerative conditions. There is growing evidence that more common systemic iron loading disorders such as hemochromatosis can also have important effects on the brain. To identify features that are common across different forms of hemochromatosis, we used microarray and real-time reverse transcription polymerase chain reaction (RT-PCR) to assess brain transcriptome profiles of transferrin receptor 2 mutant mice (Tfr2(mut)), a model of a rare type of hereditary hemochromatosis, relative to wildtype control mice. The results were compared with our previous findings in dietary iron-supplemented wildtype mice and Hfe(-/-) mice, a model of a common type of hereditary hemochromatosis. For transcripts showing significant changes relative to controls across all three models, there was perfect (100%) directional concordance (i.e. transcripts were increased in all models or decreased in all models). Comparison of the two models of hereditary hemochromatosis, which showed more pronounced changes than the dietary iron-supplemented mice, revealed numerous common molecular effects. Pathway analyses highlighted changes for genes relating to long-term depression (6.8-fold enrichment, p = 5.4 x 10(-7)) and, to a lesser extent, long-term potentiation (3.7-fold enrichment, p = 0.01), with generalized reductions in transcription of key genes from these pathways, which are involved in modulating synaptic strength and efficacy and are essential for memory and learning. The agreement across the models suggests the findings are robust and strengthens previous evidence that iron loading disorders affect the brain. Perturbations of brain phenomena such as long-term depression and long-term potentiation might partly explain neurologic symptoms reported for some hemochromatosis patients. (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.