α-tocopherol transfer protein deficiency in mice causes multi-organ deregulation of gene networks and behavioral deficits with age

Kishorchandra Gohil, Roy Godzdanker, Erin O'Roark, Bettina C. Schock, Ramesh R. Kaini, Lester Packer, Carroll E Cross, Maret G. Traber

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Functions of α-tocopherol (α-T) in vivo, other than those for fertility in females, are intensely debated. The discovery of α-T deficiency in patients with ataxia (AVED) followed by the identification of mutations in the gene encoding α-tocopherol transfer protein (TTP) in AVED patients demonstrates an essential role of α-T and TTP for normal neurological function. α-T molecular targets that account for α-T-sensitive neurological dysfunction remain to be discovered. We have used high-density oligonucleotide arrays to search for putative α-T-sensitive genes in the CNS and other tissues in an in vivo model of α-T deficiency imposed at birth by the deletion of the TTP gene hi mice. Repression of genes affecting synaptic function and myelination and induction of genes for neurodegeneration in the motor cortex of α-T-deficient mice were identified. The expression of retinoic acid-related orphan receptor alpha (ROR-α) was repressed in the cortex and adrenal glands of TTP-deficient mice. Deficiency of ROR-α causes ataxia hi mice and may account for ataxia in AVED patients. These observations suggest that some of the actions of α-T are mediated by the transcription factor ROR-α. The behavior of young TTP-null mice was essentially normal, but older mice showed inactivity, ataxia, and memory dysfunction. mRNA profiles of old α-T-deficient cerebral cortices are compatible with repressed activity of oligodendrocytes and astrocytes. In conclusion, gene-expression profiling studies have identified novel α-T-modulated genes and cells in the CNS that may be causatively linked with delayed neurodegeneration and age-related decline in behavioral repertoires.

Original languageEnglish (US)
Pages (from-to)109-126
Number of pages18
JournalAnnals of the New York Academy of Sciences
Volume1031
DOIs
StatePublished - 2004

Keywords

  • Adrenal glands
  • Ataxia
  • Gene expression
  • ROR-alpha
  • Transgenic
  • Vitamin E

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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