缺乏α-生育酚转运蛋白的小鼠迟发性共济失调：慢性氧化应激导致神经元变性的模型
Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress.
作者信息
Yokota T, Igarashi K, Uchihara T, Jishage K, Tomita H, Inaba A, Li Y, Arita M, Suzuki H, Mizusawa H, Arai H
机构信息
Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
出版信息
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15185-90. doi: 10.1073/pnas.261456098.
alpha-Tocopherol transfer protein (alpha-TTP) maintains the concentration of serum alpha-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating alpha-tocopherol export from the liver. Mutations of the alpha-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the alpha-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. Because the brain alpha-TTP functions in maintaining alpha-tocopherol levels in the brain, alpha-tocopherol was completely depleted in the alpha-TTP(-/-) mouse brain, and the neurological phenotype of alpha-TTP(-/-) mice is much more severe than that of wild-type mice when maintained on an alpha-tocopherol-deficient diet. Lipid peroxidation in alpha-TTP(-/-) mice brains showed a significant increase, especially in degenerating neurons. alpha-Tocopherol supplementation suppressed lipid peroxidation and almost completely prevented the development of neurological symptoms. This therapy almost completely corrects the abnormalities in a mouse model of human neurodegenerative disease. Moreover, alpha-TTP(-/-) mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress.
α-生育酚转运蛋白（α-TTP）通过促进肝脏中α-生育酚的输出，维持血清α-生育酚（维生素E）的浓度，α-生育酚是最有效的脂溶性抗氧化剂之一。α-TTP基因的突变与单纯维生素E缺乏性共济失调（AVED）相关。我们通过删除α-TTP基因制备了AVED模型小鼠，该小鼠在1岁后出现共济失调和视网膜变性。由于脑α-TTP在维持脑中α-生育酚水平方面发挥作用，α-TTP（-/-）小鼠脑中的α-生育酚完全耗尽，并且当在缺乏α-生育酚的饮食中饲养时，α-TTP（-/-）小鼠的神经表型比野生型小鼠严重得多。α-TTP（-/-）小鼠脑中的脂质过氧化显著增加，尤其是在退化的神经元中。补充α-生育酚可抑制脂质过氧化，并几乎完全预防神经症状的发展。这种疗法几乎完全纠正了人类神经退行性疾病小鼠模型中的异常情况。此外，α-TTP（-/-）小鼠可能被证明是由慢性氧化应激引起的迟发性、缓慢进行性神经元变性的优秀动物模型。
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