• T Yokota, K Igarashi, T Uchihara, K Jishage, H Tomita, A Inaba, Y Li, M Arita, H Suzuki, H Mizusawa, and H Arai.
• Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. tak-yokota.nuro@tmd.ac.jp
• Proc. Natl. Acad. Sci. U.S.A. 2001 Dec 18; 98 (26): 15185-90.

Abstractalpha-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.

18 keywords...

hide…