Delayed-onset ataxia in mice lacking α-tocopherol transfer protein: Model for neuronal degeneration caused by chronic oxidative stress

Abstract

␣-Tocopherol transfer protein (␣-TTP) maintains the concentration of serum ␣-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating ␣-tocopherol export from the liver. Mutations of the ␣-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the ␣-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. Because the brain ␣-TTP functions in maintaining ␣-tocopherol levels in the brain, ␣-tocopherol was completely depleted in the ␣-TTP ؊͞؊ mouse brain, and the neurological phenotype of ␣-TTP ؊͞؊ mice is much more severe than that of wild-type mice when maintained on an ␣-tocopherol-deficient diet. Lipid peroxidation in ␣-TTP ؊͞؊ mice brains showed a significant increase, especially in degenerating neurons. ␣-Tocopherol supplementation suppressed lipid peroxidation and almost completely prevented the development of neurological symptoms. This therapy almost completely corrects the abnormalities in a mouse model of human neurodegenerative disease. Moreover, ␣-TTP ؊͞؊ mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress.A taxia with isolated vitamin E deficiency (AVED) is an autosomal recessive disease, the phenotype of which is often indistinguishable from Friedreich ataxia (1), the most common hereditary ataxia in Europe and United States. We cloned the ␣-tocopherol transfer protein (␣-TTP) gene (2) and identified mutations on the ␣-TTP gene in patients with AVED (3, 4). Later, we found those same mutations on the ␣-TTP gene to be a cause of retinitis pigmentosa as well (5, 6). ␣-TTP is expressed in the brain and retina as well as in the liver, and its function still remains unclear (6, 7). Therefore, it is not known whether ␣-tocopherol deficiency is the only cause for neuronal degeneration of AVED. Here we produced a model mouse of AVED by deleting the ␣-TTP gene. The mice showed ataxia and retinal degeneration after 1 year of age, and these symptoms were reversed after ␣-tocopherol supplementation.The brain is thought to be particularly vulnerable to oxidative stress (8), and accumulating evidence suggests that oxidative stress is involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (8,9). In animal models, neuronal cell death has been induced by free radical-producing chemicals, such as paraquat (10) or N-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; ref. 11), or by knocking out the manganese superoxide dismutase gene (12). These experimentally induced neuronal degenerations develop acutely within several days and differ therefore from the cell death that occurs in human neurodegenerative diseases, which are characterized by delayed onset and slow progression over years or decades. We discuss whether the ␣-TTP Ϫ͞Ϫ mouse serves as a mouse model of age-related neuronal degeneration arising from chronic oxidative stress. Materials and MethodsG...

Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system

“…Furthermore, in contrast to the previous study which used 15 months-old mice (Leonard et al, 2002) this study used younger (5 months old) mice and showed α-T deficiency that is very severe starting at a much younger age (5 months old). Another important observation made here is that in spite of the extremely low α-T in the CNS, the young mice do not display ataxia which appears only after 9 months of age (Gohil et al, 2004;Yokota et al, 2001). Thus the development of clinical ataxia in the α-TTP-KO animals has a long latency, possibly due to the presence of unknown mechanisms that sustain normal cerebellar functions in young α-TTP-KO mice whose brains are almost devoid of α-T.…”

“…A previous study (Hosomi et al, 1998) indicated higher expression of α-TTP mRNA in the cerebellum compared to that in the cortex suggesting an inverse relationship between α-TTP mRNA expression and α-T concentrations. We also note that Yokota et al, 2001 detected very low levels of α-TTP in brain regions compared to that in liver (Yokota et al, 2001); however α-T concentration in the two organs are very similar, further suggesting a lack of causal relationship between α-TTP expression and whole tissue α-T concentrations. It is also noteworthy that α-TTP was not detected in WT-heart (Yokota et al, 2001) but α-T concentrations in WT-hearts hearts are similar to those of WT-livers (Fig.…”

“…Previous studies have shown that cerebellum and cortex from α-TTP-KO mice have very low or undetectable concentrations of α-T (Gohil et al, 2004;Gohil et al, 2003;Leonard et al, 2002;Yokota et al, 2001). Unlike previous studies we have determined α-T in several brain regions.…”

“…This is vividly demonstrated in Ataxia with Vitamin E Deficiency (AVED) patients who present with neurological symptoms of varying severity (Cavalier et al, 1998;Gotoda et al, 1995;Schuelke et al, 1999;Tamaru et al, 1997). Neurological deficits similar to those of the AVED subjects are also observed in transgenic mice with a deletion of the α-TTP gene (Yokota et al, 2001;Yokota et al, 1987). Furthermore, cerebral cortex of α-TTP-knockout (α-TTP-KO) mice has been reported to display attenuated electrophysiological activity compared to the activity displayed by WT mice.…”

“…The model may also have utility in testing neuroprotective effects of other members of vitamin E family such as tocotrienols (Sen et al, 2007) An understanding of the role of α-TTP in brain would be aided by relating α-T levels in the α-TTP-KO mice with biochemical parameters. Yokota et.al (Yokota et al, 2001) have shown that α-T is very low in two brain regions and that the levels reached quantifiable levels only after feeding a diet high in vitamin E. To characterize the role of α-TTP gene in the retention, distribution and biological actions of α-T in the CNS, we have determined α-T, cholesterol, total glutathione and the expression of α-TTP gene from several brain regions. We have also examined whether gender influences brain concentrations of the three compounds.…”