Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in α-tocopherol transfer protein

Kishorchandra Gohil, Bettina C. Schock, Abhishek A. Chakraborty, Yuko Terasawa, Jacob Raber, Robert V. Farese, Lester Packer, Carroll E Cross, Maret G. Traber

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Alpha-tocopherol transfer protein (TTP) regulates the retention and secretion of α-tocopherol (α-T) by the liver. Deletion of the TTP gene (Ttpa) in mice results in systemic deficiency of α-T and neurological dysfunctions described in patients with mutated Ttpa. We have explored genome-wide changes in mRNAs from brain cortex and liver of Ttpa-deficient (Ttpa-/-) mice and wild-type (Ttpa+/+) mice. Selective inductions of genes regulated by antioxidant response elements were detected in Ttpa-/- livers compared to Ttpa+/+ livers, suggesting increased oxidant stress in Ttpa-/- livers. The activation of cell proliferation pathways in Ttpa-/- livers was indicated by the induction of genes that encode growth factor-binding proteins, mitogen-activated protein kinase kinase 3, and apoptosis inhibitor 6. The induction of synuclein-α and repression of synuclein-β genes was detected in Ttpa-/- cortex. This may predispose Ttpa-/- cortex to increased formation of synuclein-α aggregates and Lewy body, often associated with oxidant stress. Cortex of Ttpa-/- mice revealed repression of genes encoding synaptic proteins, protein kinase C family members, and myelin proteins. A 13-fold decrease in the expression of retinoic acid receptor-related orphan receptor-α mRNA predicts staggerer-like phenotype (ataxia and deficits of motor coordination) of Ttpa-/- mice. The repression of specific genes that determine synaptic plasticity and neuronal development may account for suppressed electrophysiological activities of cortex and impaired behavior in Ttpa -/- mice.

Original languageEnglish (US)
Pages (from-to)1343-1354
Number of pages12
JournalFree Radical Biology and Medicine
Volume35
Issue number11
DOIs
StatePublished - Dec 1 2003

Keywords

  • Antioxidant
  • Anxiety
  • Free radicals
  • Long-term potentiation
  • Neurodegeneration
  • Oligonucleotide arrays
  • Synapse
  • Vitamin E

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

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