Delayed-onset ataxia in mice lacking α-tocopherol transfer protein:: Model for neuronal degeneration caused by chronic oxidative stress

被引：213

作者：

Yokota, T ^{[1
]}

Igarashi, K

Uchihara, T

Jishage, K

Tomita, H

Inaba, A

Li, Y

Arita, M

Suzuki, H

Mizusawa, H

Arai, H

机构：

[1] Tokyo Med & Dent Univ, Dept Neurol, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138519, Japan

[2] Univ Tokyo, Dept Hlth Chem, Bunkyo Ku, Tokyo 1130013, Japan

[3] Tokyo Metropolitan Inst Neurosci, Fuchu, Tokyo 1838526, Japan

[4] Chugai Pharmaceut Co Ltd, Pharmaceut Technol Lab, Shizuoka 4128513, Japan

[5] Tohoku Univ, Dept Ophthalmol, Aoba Ku, Sendai, Miyagi 9808574, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2001年 / 98卷 / 26期

关键词：

D O I：

10.1073/pnas.261456098

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：15185 / 15190

页数：6

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