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

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.