α‐Tocopherol Transfer Protein Deficiency in Mice Causes Multi‐Organ Deregulation of Gene Networks and Behavioral Deficits with Age

Abstract

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

Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system

“…Furthermore, cerebral cortex of α-TTP-knockout (α-TTP-KO) mice has been reported to display attenuated electrophysiological activity compared to the activity displayed by WT mice. Genome-wide mRNA expression analysis of the cerebral cortex from young, asymptomatic α-TTP-KO mice suggest a role for α-T in myelination and synaptic functions in the CNS (Gohil et al, 2004;Gohil et al, 2003). Similar observations were reported in rats fed α-T deficient diets (Hyland et al, 2006).…”

“…Furthermore, in contrast to the previous study which used 15 months-old mice (Leonard et al, 2002) this study used younger (5 months old) mice and showed α-T deficiency that is very severe starting at a much younger age (5 months old). Another important observation made here is that in spite of the extremely low α-T in the CNS, the young mice do not display ataxia which appears only after 9 months of age (Gohil et al, 2004;Yokota et al, 2001). Thus the development of clinical ataxia in the α-TTP-KO animals has a long latency, possibly due to the presence of unknown mechanisms that sustain normal cerebellar functions in young α-TTP-KO mice whose brains are almost devoid of α-T.…”

“…Previous studies have shown that cerebellum and cortex from α-TTP-KO mice have very low or undetectable concentrations of α-T (Gohil et al, 2004;Gohil et al, 2003;Leonard et al, 2002;Yokota et al, 2001). Unlike previous studies we have determined α-T in several brain regions.…”

Novel Transcriptional Activities of Vitamin E: Inhibition of Cholesterol Biosynthesis

“…Moreover, αTOH was shown to regulate the expression levels of several mRNAs and proteins, such as collagen α1 (9), the scavenger receptors SR-BI (10) and CD36 (11,12), α-tropomyosin (13), the nuclear receptor PPARγ (14), and the adhesion molecule VCAM-I (15). These anecdotal observations were further supported by several studies that documented genomic responses to vitamin E using expression-profiling § To whom correspondence should be addressed at: School of Medicine, Case Western Reserve University, WG48, 2109 Adelbert Rd., Cleveland, [16][17][18][19][20][21][22][23]. However, interpretation of such analyses is complicated by the known genomic responses to changes in cellular redox status (24).…”

“…approaches (16)(17)(18)(19)(20)(21)(22)(23). However, interpretation of such analyses is complicated by the known genomic responses to changes in cellular redox status (24).…”