Delayed-onset ataxia in mice lacking alpha -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.
Yokota
T
T
Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. tak-yokota.nuro@tmd.ac.jp
Igarashi
K
K
Uchihara
T
T
Jishage
K
K
Tomita
H
H
Inaba
A
A
Li
Y
Y
Arita
M
M
Suzuki
H
H
Mizusawa
H
H
Arai
H
H
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
D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein