Gohil Kishorchandra, Schock Bettina C, Chakraborty Abhishek A, Terasawa Yuko, Raber Jacob, Farese Robert V, Packer Lester, Cross Carroll E, Traber Maret G
Center for Comparative Respiratory and Medicine, Department of Internal Medicine, University of California, Davis, CA 95616, USA.
Free Radic Biol Med. 2003 Dec 1;35(11):1343-54. doi: 10.1016/s0891-5849(03)00509-4.
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.
α-生育酚转运蛋白（TTP）调节肝脏对α-生育酚（α-T）的潴留和分泌。小鼠中TTP基因（Ttpa）的缺失导致α-T全身性缺乏以及Ttpa突变患者中所描述的神经功能障碍。我们探究了Ttpa基因缺陷型（Ttpa(-/-)）小鼠和野生型（Ttpa(+/+)）小鼠大脑皮层和肝脏中mRNA的全基因组变化。与Ttpa(+/+)肝脏相比，在Ttpa(-/-)肝脏中检测到了由抗氧化反应元件调控的基因的选择性诱导，这表明Ttpa(-/-)肝脏中的氧化应激增加。Ttpa(-/-)肝脏中细胞增殖途径的激活表现为编码生长因子结合蛋白、丝裂原活化蛋白激酶激酶3和凋亡抑制因子6的基因的诱导。在Ttpa(-/-)皮层中检测到了α-突触核蛋白基因的诱导和β-突触核蛋白基因的抑制。这可能使Ttpa(-/-)皮层更容易形成α-突触核蛋白聚集体和路易小体，这通常与氧化应激有关。Ttpa(-/-)小鼠的皮层显示出编码突触蛋白、蛋白激酶C家族成员和髓鞘蛋白的基因受到抑制。视黄酸受体相关孤儿受体-α mRNA表达下降13倍预示着Ttpa(-/-)小鼠具有蹒跚样表型（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是Ttpa(-/-)小鼠皮层电生理活动受抑制和行为受损（的原因）。
