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Abetalipoproteinemia

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Herbert J. Kayden – One of the best experts on this subject based on the ideXlab platform.

R P Copp – One of the best experts on this subject based on the ideXlab platform.

  • Localization of alpha-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders.
    Brain research, 1999
    Co-Authors: R P Copp, T Wisniewski, Fayçal Hentati, A Larnaout, M Ben Hamida, Herbert J. Kayden
    Abstract:

    Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer’s disease (AD), Down’s syndrome (DS), cholestatic liver disease (CLD) and Abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of Abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.

  • localization of α tocopherol transfer protein in the brains of patients with ataxia with vitamin e deficiency and other oxidative stress related neurodegenerative disorders
    Brain Research, 1999
    Co-Authors: R P Copp, T Wisniewski, Fayçal Hentati, A Larnaout, Ben M Hamida, Herbert J. Kayden
    Abstract:

    Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer’s disease (AD), Down’s syndrome (DS), cholestatic liver disease (CLD) and Abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of Abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.

Lawrence P. Aggerbeck – One of the best experts on this subject based on the ideXlab platform.

Agnes Sassolas – One of the best experts on this subject based on the ideXlab platform.

David A Gordon – One of the best experts on this subject based on the ideXlab platform.

  • a novel Abetalipoproteinemia genotype identification of a missense mutation in the 97 kda subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase
    Journal of Biological Chemistry, 1996
    Co-Authors: Edward F Rehberg, Lawrence P. Aggerbeck, Bernadette Kienzle, Laura Blinderman, John R. Wetterau, Marieelisabeth Samsonbouma, Haris Jamil, David A Gordon
    Abstract:

    The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the ubiquitous multifunctional protein, protein disulfide isomerase, and a unique 97-kDa subunit. Mutations that lead to the absence of a functional 97-kDa subunit cause Abetalipoproteinemia, an autosomal recessive disease characterized by a defect in the assembly and secretion of apolipoprotein B (apoB) containing lipoproteins. Previous studies of abetalipoproteinemic patient, C.L., showed that the 97-kDa subunit was undetectable. In this report, [35S]methionine labeling showed that this tissue was capable of synthesizing the 97-kDa MTP subunit. Electrophoretic analysis showed two bands, one with a molecular mass of the wild type 97-kDa subunit and the other with a slightly lower molecular weight. Sequence analysis of cDNAs from additional intestinal biopsies showed this patient to be a compound heterozygote. One allele contained a perfect in-frame deletion of exon 10, explaining the lower molecular weight band. cDNAs of the second allele were found to contain 3 missense mutations: His297 –> Gln, Asp384 –> Ala, and Arg540 –> His. Transient expression of each mutant showed that only the Arg540 –> His mutant was non-functional based upon its inability to reconstitute apoB secretion in a cell culture system. The other amino acid changes are silent polymorphisms. High level coexpression in a baculovirus system of the wild type 97-kDa subunit or the Arg540 –> His mutant along with human protein disulfide isomerase showed that the wild type was capable of forming an active MTP complex while the mutant was not. Biochemical analysis of lysates from these cells showed that the Arg to His conversion interrupted the interaction between the 97-kDa subunit and protein disulfide isomerase. Replacement of Arg540 with a lysine residue maintained the ability of the 97-kDa subunit to complex with protein disulfide isomerase and form the active MTP holoprotein. These results indicate that a positively charged amino acid at position 540 in the 97-kDa subunit is critical for the productive association with protein disulfide isomerase. Of the 13 mutant MTP 97-kDa subunit alleles described to date, this is the first encoding a missense mutamutation.

  • a 30 amino acid truncation of the microsomal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide isomerase and causes Abetalipoproteinemia
    Journal of Biological Chemistry, 1995
    Co-Authors: Beverly Ricci, Richard E. Gregg, Daru Young Sharp, Edward Orourke, Bernadette Kienzle, Laura Blinderman, David A Gordon, Connie Smithmonroy, Gordon William Robinson, Daniel J. Rader
    Abstract:

    The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the multifunctional enzyme, protein disulfide-isomerase, and a unique large, 97 kDa, subunit. It is found as a soluble protein within the lumen of the endoplasmic retireticulum of liver and intestine and is required for the assembly of very low density lipoproteins and chylomicrons. Mutations in MTP which result in an absence of MTP function have been shown to cause Abetalipoproteinemia. Here, the gene encoding the MTP 97-kDa subunit of an abetalipoproteinemic subject, which we have previously demonstrated lacks MTP activity and protein (Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., and Gregg, R. E.(1992) Science 258, 999-1001), was isolated and sequenced. A nonsense mutamutation, which predicts the truncation of the protein by 30 amino acids, was identified. To investigate if this apparently subtle change in MTP could explain the observed absence of MTP, protein disulfide-isomerase was co-expressed with either the normal or mutant MTP 97-kDa subunit in Sf9 insect cells using a baculovirus expression system. Although there were high levels of expression of both the normal and mutant forms of the MTP 97-kDA subunit, only the normal subunit was able to form a stable, soluble complex with protein disulfide-isomerase. These results indicate that the carboxyl-terminal 30 amino acids of the MTP 97-kDa subunit plays an important role in its interaction with protein disulfide-isomerase.