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 language | English (US) |
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Pages (from-to) | 1343-1354 |
Number of pages | 12 |
Journal | Free Radical Biology and Medicine |
Volume | 35 |
Issue number | 11 |
DOIs | |
State | Published - Dec 1 2003 |
Externally published | Yes |
Keywords
- Antioxidant
- Anxiety
- Free radicals
- Long-term potentiation
- Neurodegeneration
- Oligonucleotide arrays
- Synapse
- Vitamin E
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)