Delayed-onset ataxia in mice lacking α-tocopherol transfer protein

Model for neuronal degeneration caused by chronic oxidative stress

Takanori Yokota, Keiji Igarashi, Toshiki Uchihara, Kou Ichi Jishage, Hiroshi Tomita, Akira Inaba, Yi Li, Makoto Arita, Hiroshi Suzuki, Hidehiro Mizusawa, Hiroyuki Arai

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

α-Tocopherol transfer protein (α-TTP) maintains the concentration of serum α-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating α-tocopherol export from the liver. Mutations of the α-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the α-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. Because the brain α-TTP functions in maintaining α-tocopherol levels in the brain, α-tocopherol was completely depleted in the α-TTP-/- mouse brain, and the neurological phenotype of α-TTP-/- mice is much more severe than that of wild-type mice when maintained on an α-tocopherol-deficient diet. Lipid peroxidation in α-TTP-/- mice brains showed a significant increase, especially in degenerating neurons. α-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, α-TTP-/- mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress.

Original languageEnglish
Pages (from-to)15185-15190
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number26
DOIs
Publication statusPublished - 2001 Dec 18
Externally publishedYes

Fingerprint

Tocopherols
Ataxia
Oxidative Stress
Proteins
Brain
Lipid Peroxidation
Retinal Degeneration
thymidine 5'-triphosphate
Vitamin E
Neurodegenerative Diseases
Genes
Animal Models
Antioxidants
Fats
Diet
Phenotype
Neurons
Mutation
Liver
Serum

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Delayed-onset ataxia in mice lacking α-tocopherol transfer protein : Model for neuronal degeneration caused by chronic oxidative stress. / Yokota, Takanori; Igarashi, Keiji; Uchihara, Toshiki; Jishage, Kou Ichi; Tomita, Hiroshi; Inaba, Akira; Li, Yi; Arita, Makoto; Suzuki, Hiroshi; Mizusawa, Hidehiro; Arai, Hiroyuki.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 26, 18.12.2001, p. 15185-15190.

Research output: Contribution to journalArticle

Yokota, Takanori ; Igarashi, Keiji ; Uchihara, Toshiki ; Jishage, Kou Ichi ; Tomita, Hiroshi ; Inaba, Akira ; Li, Yi ; Arita, Makoto ; Suzuki, Hiroshi ; Mizusawa, Hidehiro ; Arai, Hiroyuki. / Delayed-onset ataxia in mice lacking α-tocopherol transfer protein : Model for neuronal degeneration caused by chronic oxidative stress. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 26. pp. 15185-15190.
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