α-Tocopherol (vitamin E) is an essential dietary antioxidant with important neuroprotective functions. α-Tocopherol deficiency manifests primarily in neurological pathologies, notably cerebellar dysfunctions such as spinocerebellar ataxia. To study the roles of α-tocopherol in the cerebellum, we used the α-tocopherol transfer protein for the murine version (Ttpa(-/)(-)) mice which lack the α-tocopherol transfer protein (TTP) and are a faithful model of vitamin E deficiency and oxidative stress. When fed vitamin E-deficient diet, Ttpa(-/)(-) mice had un-detectable levels of α-tocopherol in plasma and several brain regions. Dietary supplementation with α-tocopherol normalized plasma levels of the vitamin, but only modestly increased its levels in the cerebellum and prefrontal cortex, indicating a critical function of brain TTP. Vitamin E deficiency caused an increase in cerebellar oxidative stress evidenced by increased protein nitrosylation, which was prevented by dietary supplementation with the vitamin. Concomitantly, vitamin E deficiency precipitated cellular atrophy and diminished dendritic branching of Purkinje neurons, the predominant output regulator of the cerebellar cortex. The anatomic decline induced by vitamin E deficiency was paralleled by behavioral deficits in motor coordination and cognitive functions that were normalized upon vitamin E supplementation. These observations underscore the essential role of vitamin E and TTP in maintaining CNS function, and support the notion that α-tocopherol supplementation may comprise an effective intervention in oxidative stress-related neurological disorders.
Keywords: 3-NT; 3-nitrotyrosine; AD; ANOVA; AVED; Alzheimer’s disease; CS; NPC; Niemann Pick disease type C; Purkinje neuron; SCA; TBARS; TTP; TTPA; Ttpa; US; analysis of variance; ataxia; ataxia with vitamin E deficiency; cerebellum; conditioned stimulus; oxidative stress; spinocerebellar ataxia; t-HODE; thiobarbituric acid reactive substances; tocopherol; total hydroxyoctadecadienoic acid; unconditioned stimulus; vitamin E; α-tocopherol transfer protein; α-tocopherol transfer protein gene for the human version; α-tocopherol transfer protein gene for the murine version.
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