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

• Published in: Free radical biology & medicine 2003-12, Vol.35 (11), p.1343-1354
• Main Authors: Gohil, Kishorchandra, Schock, Bettina C, Chakraborty, Abhishek A, Terasawa, Yuko, Raber, Jacob, Farese, Robert V, Packer, Lester, Cross, Carroll E, Traber, Maret G
• Format: Article
• Language: English
• Subjects: a-tocopherol transfer protein; Animals; Antioxidant; Anxiety; apoptosis inhibitor 6; Brain - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Division; DNA - metabolism; Female; Free radicals; Gene Deletion; Gene Expression Regulation; growth factor-binding protein; Liver - metabolism; Long-term potentiation; Male; MAP Kinase Kinase 3; Maze Learning; MEKK3 protein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases - metabolism; Models, Biological; Myelin Sheath - metabolism; Neurodegeneration; Neurodegenerative Diseases - metabolism; Nuclear Receptor Subfamily 1, Group F, Member 1; Oligonucleotide Array Sequence Analysis; Oligonucleotide arrays; orphan nuclear receptor ROR-^a; Oxidants; Protein Kinase C - metabolism; Protein-Tyrosine Kinases - metabolism; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid - metabolism; RNA - metabolism; RNA, Messenger - metabolism; Synapse; Trans-Activators; Transcription Factors; Ttpa gene; Vitamin E
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/S0891-5849(03)00509-4

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.