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.