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PNAS | December 18, 2001 | vol. 98 | no. 26 | 15185-15190
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From the Cover
Medical Sciences
 Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: Model for neuronal degeneration caused by chronic oxidative stress

Takanori Yokota*,dagger , Keiji IgarashiDagger , Toshiki Uchihara§, Kou-ichi Jishage, Hiroshi Tomita||, Akira Inaba*, Yi Li*, Makoto AritaDagger , Hiroshi Suzuki, Hidehiro Mizusawa*, and Hiroyuki Araidagger ,Dagger

* Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Dagger  Department of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunyo-ku, Tokyo 113-0013, Japan; § Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu-shi, Tokyo 183-8526, Japan;  Pharmaceutical Technology Laboratory, Chugai Pharmaceutical Company, Ltd., 1-135 Komakado, Gotenba, Shizuoka 412-8513, Japan; and || Department of Ophthalmology, Tohoku University, 1-1 Seiryo-cho, Aoba-ku, Miyagi 980-8574, Japan

Edited by E. R. Stadtman, National Institutes of Health, Bethesda, MD, and approved October 25, 2001 (received for review August 29, 2001)

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.

dagger To whom reprint requests may be addressed. E-mail: tak-yokota.nuro{at}tmd.ac.jp or harai{at}mol.f.u-tokyo.ac.jp.

www.pnas.org/cgi/doi/10.1073/pnas.261456098
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