Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in alpha-tocopherol transfer protein.
Alpha-tocopherol transfer protein (TTP) regulates the retention and secretion of alpha-tocopherol (alpha-T) by the liver. Deletion of the TTP gene (Ttpa) in mice results in systemic deficiency of alpha-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-alpha and repression of synuclein-beta genes was detected in Ttpa(-/-) cortex. This may predispose Ttpa(-/-) cortex to increased formation of synuclein-alpha 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-alpha 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.
Gohil
Kishorchandra
K
Center for Comparative Respiratory and Medicine, Department of Internal Medicine, University of California, Davis, CA 95616, USA. kgohil@ucdavis.edu
Schock
Bettina C
BC
Chakraborty
Abhishek A
AA
Terasawa
Yuko
Y
Raber
Jacob
J
Farese
Robert V
RV
Packer
Lester
L
Cross
Carroll E
CE
Traber
Maret G
MG
D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division; D004247:DNA / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism; D048371:MAP Kinase Kinase 3; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009186:Myelin Sheath / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors
D002352:Carrier Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D016877:Oxidants; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D014157:Transcription Factors; C017763:alpha-tocopherol transfer protein; D012313:RNA; D004247:DNA; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases