Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in α-tocopherol transfer protein
Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in α-tocopherol transfer protein
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DOI：
10.1016/s0891-5849(03)00509-4
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发表时间：
2003-12-01
影响因子：
7.4
通讯作者：
Traber, MG
中科院分区：
文献类型：
--
作者：
Gohil, K;Schock, BC;Traber, MG
α -生育酚转移蛋白（TTP）调节肝脏对α -生育酚（α -t）的保留和分泌。小鼠中Ttpa基因的缺失会导致α - t的全身性缺乏和Ttpa突变患者所描述的神经功能障碍。我们探索了Ttpa缺陷（Ttpa(-/-)）小鼠和野生型（Ttpa(+/+)）小鼠脑皮质和肝脏mrna的全基因组变化。与Ttpa（+/+）肝脏相比，Ttpa（-/-）肝脏中检测到抗氧化反应元件调控基因的选择性诱导，表明Ttpa（-/-）肝脏中氧化应激增加。通过诱导编码生长因子结合蛋白、丝裂原活化蛋白激酶激酶3和凋亡抑制剂6的基因，Ttpa（-/-）肝脏细胞增殖途径被激活。在Ttpa（-/-）皮层中检测到synuclein- α的诱导和synuclein- β基因的抑制。这可能使Ttpa（-/-）皮层增加突触核蛋白- α聚集体和路易体的形成，通常与氧化应激有关。Ttpa（-/-）小鼠的皮层显示编码突触蛋白、蛋白激酶C家族成员和髓磷脂蛋白的基因受到抑制。维甲酸受体相关孤儿受体α mRNA表达减少13倍，可预测Ttpa（-/-）小鼠的错开样表型（共济失调和运动协调缺陷）。决定突触可塑性和神经元发育的特定基因的抑制可能解释了Ttpa（-/-）小鼠皮层电生理活动的抑制和行为受损。(C) 2003 Elsevier Inc.
Alpha-tocopherol transfer protein (TTP) regulates the retention and secretion of alpha-tocopherol (alpha-T) by the liver. Deletion of the TTP gene (Ttpa) in mice results in systemic deficiency of alpha-T and neurological dysfunctions described in patients with mutated Ttpa. We have explored genome-wide changes in mRNAs from brain cortex and liver of Ttpa-deficient (Ttpa(-/-)) mice and wild-type (Ttpa(+/+)) mice. Selective inductions of genes regulated by antioxidant response elements were detected in Ttpa(-/-) livers compared to Ttpa(+/+) livers, suggesting increased oxidant stress in Ttpa(-/-) livers. The activation of cell proliferation pathways in Ttpa(-/-) livers was indicated by the induction of genes that encode growth factor-binding proteins, mitogen-activated protein kinase kinase 3, and apoptosis inhibitor 6. The induction of synuclein-alpha and repression of synuclein-beta genes was detected in Ttpa(-/-) cortex. This may predispose Ttpa(-/-) cortex to increased formation of synuclein-alpha aggregates and Lewy body, often associated with oxidant stress. Cortex of Ttpa(-/-) mice revealed repression of genes encoding synaptic proteins, protein kinase C family members, and myelin proteins. A 13-fold decrease in the expression of retinoic acid receptor-related orphan receptor-alpha mRNA predicts staggerer-like phenotype (ataxia and deficits of motor coordination) of Ttpa(-/-) mice. The repression of specific genes that determine synaptic plasticity and neuronal development may account for suppressed electrophysiological activities of cortex and impaired behavior in Ttpa(-/-) mice. (C) 2003 Elsevier Inc.