title: Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress.
abstract: 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.
authors.affiliation: Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. tak-yokota.nuro@tmd.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Yokota
authors.forename: K
authors.initials: K
authors.lastname: Igarashi
authors.forename: T
authors.initials: T
authors.lastname: Uchihara
authors.forename: K
authors.initials: K
authors.lastname: Jishage
authors.forename: H
authors.initials: H
authors.lastname: Tomita
authors.forename: A
authors.initials: A
authors.lastname: Inaba
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Arita
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Mizusawa
authors.forename: H
authors.initials: H
authors.lastname: Arai
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics*; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008959:Models, Neurological; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein