Localization of α-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders

Copp, Richard P.; Wısnıewskı, Thomas; Hentati, Fayçal; Larnaout, A.; Hamida, M. Ben; Kayden, Herbert J.

doi:10.1016/s0006-8993(99)01090-2

Cited by 121 publications

(90 citation statements)

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“…Previous studies have reported such discrete cellular localization of α-TTP. For example, the occurrence of α-TTP has been reported in rat cerebellar Bergman glia (Hosomi et al, 1998) and in Purkinje cells of AVED patients, in selected cells of patients with oxidative stress related to neurodegeneration (Copp et al, 1999) and in trophoblast, fetal capillaries, endothelium and amnion epithelium of human term placenta (Muller-Schmehl et al, 2004). However, the presence of a few α-TTP expressing cells in a tissue may not account for bulk α-T determined in whole tissue homogenates.…”

Section: Tissue α-T Concentrations Are Not Directly Correlated With αmentioning

confidence: 99%

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

et al. 2008

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Ataxia with vitamin E deficiency is caused by mutations in α-tocopherol transfer protein (α-TTP) gene and it can be experimentally generated in mice by α-TTP gene inactivation (α-TTP-KO). This study compared α-tocopherol (α-T) concentrations of five brain regions and of four peripheral organs from 5 months old, male and female, wild-type (WT) and α-TTP-KO mice. All brain regions of female WT mice contained significantly higher α-T than those from WT males. α-T concentration in the cerebellum was significantly lower than that in other brain regions of WT mice. These sex and regional differences in brain α-T concentrations do not appear to be determined by α-TTP expression which was undetectable in all brain regions. All the brain regions of α-TTP-KO mice were severely depleted in α-T. The concentration of another endogenous antioxidant, total glutathione, was unaffected by gender but was decreased slightly but significantly in most brain regions of α-TTP-KO mice. The results show that both gender and the hepatic α-TTP, but not brain α-TTP gene expression are important in determining α-T concentrations within the brain. Interestingly, functional abnormality (ataxia) develops only very late in α-TTP-KO mice in spite of the severe α-tocopherol deficiency in brain starting at an early age.

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Section: Tissue α-T Concentrations Are Not Directly Correlated With αmentioning

confidence: 99%

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

et al. 2008

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“…Son inocuité en cas d'apports massifs (jusqu'à 100 fois l'apport nutritionnel conseillé) est inhabituelle si l'on se réfère à d'autres micro-nutriments, mais s'explique par l'existence d'une fonction hépatique spécifique de « recyclage » de la forme naturelle de l'alpha-tocophérol exercée par l'ATTP et d'un système efficace de régénération de la forme oxydée chromanoxyle. Il se pourrait que d'autres protéines de tranfert de la vitamine E existent, avec une distribution tissulaire plus large que celle de l'ATTP [77,78].…”

Section: Resultsunclassified

La vitamine E : état actuel des connaissances, rôle dans la prévention cardio-vasculaire, biodisponibilité

Léger¹

2000

OCL

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La vitamine E : état actuel des connaissances, rôle dans la prévention cardio-vasculaire, biodisponibilitéVitamin E: current state of knowledge, role in the prevention of cardiovascular disease, bioavailability Oléagineux, Corps Gras, Lipides. Volume 7, Numéro 3, 258-65, Mai -Juin 2000, Dossier : Les vitamines liposolubles Auteur(s) : Claude-Louis LEGER Résumé : Les propriétés anti-oxydantes de la vitamine E -qui font l'objet d'une large majorité des travaux effectués actuellement sur cette vitamine -n'ont été reconnues qu'au cours des années 50. La vitamine E avait cependant été découverte quelque trente ans plus tôt. Mais, paradoxe intéressant, son rôle comme micronutriment essentiel n'a été reconnu qu'à la fin des années 60. Cette vitamine jouit d'un certain nombre de particularités. C'est l'anti-oxydant majeur des milieux lipidiques (huiles, membranes biologiques, lipoprotéines). Elle présente différentes formes moléculaires : des vitamères a, b, g et d, chaque vitamère existant sous différentes formes stéréo-isomériques dont une seule, parmi les huit formes possibles, est naturelle : la forme RRR (figure 1). La molécule présente deux parties : un noyau 6-OH-chromane qui possède la fonction anti-oxydante, et une chaîne latérale à 16 atomes de carbone de structure isoprénique, celle-ci définissant deux grandes familles : les tocophérols à chaîne latérale saturée et les tocotriénols avec une chaîne latérale présentant trois doubles liaisons. Cette chaîne latérale détermine la lipophilicité et la stéréochimie de la molécule. C'est la stéréochimie de la molécule qui détermine à son tour la reconnaissance préférentielle de la forme RRR-a-tocophérol par un transporteur hépatique spécifique dont le rôle physiologique est aujourd'hui reconnu. Chacune de ces formes moléculaires (le nombre théorique est de 64) peut être caractérisée par une activité vitaminique E, définie par référence au pouvoir anti-abortif chez la rate gestante. Les tableaux 1 et 2 donnent cette activité en fonction de la molécule considérée. La forme naturelle de l'a-tocophérol, le RRR-a-tocophérol, possède l'activité la plus élevée, alors que la stéréo-isomérie de la molécule n'exerce aucun effet sur ses propriétés anti-oxydantes. Enfin, c'est à partir de la fin des années 70 et du début des années 80 que les propriétés cellulaires régulatrices de la vitamine E vont être révélées. Elles font aujourd'hui l'objet de recherches actives sur les cascades de signalisation affectant différentes fonctions cellulaires. Elles ne semblent pas corrélées aux propriétés anti-oxydantes mais pourraient impliquer des étapes de reconnaissance stéréo-dépendantes.Summary: Vitamin E is a generic term for a group of substances with a 6-OH-chroman nucleus. The most common one is the a-tocophérol and its natural form, the RRR-a-tocophérol stereoisomer. It has numerous functions. The antioxidant function is the most thoroughly studied and the best known. The role played by oxidized LDL -and its oxidation -in atherosclerosis and the fact that vitamin E is the major antiox...

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“…Further homeostatic control is provided by the fact that TTP's stability in cells is modulated by ubiquitination which, in turn, is regulated by ␣-tocopherol (61). Finally, TTP is also expressed in the brain (25,62) and the placenta (28,39,63). It is likely that in these locations, TTP provides an additional layer of regulation that maintains local ␣-tocopherol sufficiency in the most sensitive tissues, i.e.…”

Section: Discussionmentioning

confidence: 99%

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

Chung¹,

Ghelfi

Atkinson

et al. 2016

Journal of Biological Chemistry

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␣-Tocopherol (vitamin E) is an essential nutrient for all vertebrates. From the eight naturally occurring members of the vitamin E family, ␣-tocopherol is the most biologically active species and is selectively retained in tissues. The hepatic ␣-tocopherol transfer protein (TTP) preferentially selects dietary ␣-tocopherol and facilitates its transport through the hepatocyte and its secretion to the circulation. In doing so, TTP regulates body-wide levels of ␣-tocopherol. The mechanisms by which TTP facilitates ␣-tocopherol trafficking in hepatocytes are poorly understood. We found that the intracellular localization of TTP in hepatocytes is dynamic and responds to the presence of ␣-tocopherol. In the absence of the vitamin, TTP is localized to perinuclear vesicles that harbor CD71, transferrin, and Rab8, markers of the recycling endosomes. Upon treatment with ␣-tocopherol, TTP-and ␣-tocopherol-containing vesicles translocate to the plasma membrane, prior to secretion of the vitamin to the exterior of the cells. The change in TTP localization is specific to ␣-tocopherol and is time-and dose-dependent. The aberrant intracellular localization patterns of lipid binding-defective TTP mutants highlight the importance of protein-lipid interaction in the transport of ␣-tocopherol. These findings provide the basis for a proposed mechanistic model that describes TTP-facilitated trafficking of ␣-tocopherol through hepatocytes.Vitamin E is a plant-derived lipid that was discovered as a dietary component vital for female fertility in rodents (1) and for neuronal health in humans (2). Eight vitamin E forms are synthesized by plants, differing in the degree of methylation of the chromanol ring and the saturation of the isoprenoid side chain (3). Of the eight naturally occurring forms of vitamin E, ␣-tocopherol exhibits the most potent biological activity in preventing deficiency-induced reproductive failure in rodents (4, 5). ␣-Tocopherol's efficacy in scavenging free radicals (i.e. functioning as an antioxidant) is thought to underlie its critical roles in health (6 -8), but additional redox-independent actions have been recently proposed (9).The major regulator of vitamin E status is the ␣-tocopherol transfer protein (TTP), 2 and mutations in the TTPA gene cause heritable vitamin E deficiency. In humans, mutations in the TTPA gene cause systemic vitamin E deficiency accompanied by neurological compromise, primarily spinocerebellar ataxia (10 -17). Patients afflicted with this disorder (ataxia with vitamin E deficiency; OMIM 277460) present with debilitating neurodegeneration, the severity of which depends on the specific mutation's effect on TTP's biochemical activity (18,19). Lifelong vitamin E supplementation can delay or reverse disease progression, especially when patients are treated in earlier stages (20,21). Disruption of the TtpA gene in mice recapitulated the human ataxia with vitamin E deficiency disorder (22).TTP is expressed at high levels in parenchymal cells of the liver (23, 24), but low level expression has b...

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Localization of α-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders

Cited by 121 publications

References 38 publications

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

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

La vitamine E : état actuel des connaissances, rôle dans la prévention cardio-vasculaire, biodisponibilité

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

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