Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy.

Fournier, B.; Saudubray, Jean Marie; Bénichou, Bernard; Lyonnet, Stanislas; Münnich, Arnold; Clevers, Hans; Poll-Thé, Bwee Tien

doi:10.1172/jci117365

Cited by 72 publications

(47 citation statements)

References 23 publications

(19 reference statements)

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“…One of these peroxisomal disorders is pseudoneonatal adrenoleukodystrophy (P-NALD), caused by ACOX1 deficiency. 18 The ACOX1 enzyme is encoded by a single gene, which generates two splice variants, including exon 3a or exon 3b, respectively, 19,20 leading to the synthesis of two protein isoforms ACOX1a or ACOX1b. 21 A single homozygous mutation in exon 3b results in the development of the P-NALD disease, 22 suggesting different substrate specificities of the two ACOX1 isoforms.…”

mentioning

confidence: 99%

Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

Vluggens

Andreoletti

Viswakarma

et al. 2010

Laboratory Investigation

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Disruption of the peroxisomal acyl-CoA oxidase 1 (Acox1) gene in the mouse results in the development of severe microvesicular hepatic steatosis and sustained activation of peroxisome proliferator-activated receptor-a (PPARa). These mice manifest spontaneous massive peroxisome proliferation in regenerating hepatocytes and eventually develop hepatocellular carcinomas. Human ACOX1, the first and rate-limiting enzyme of the peroxisomal b-oxidation pathway, has two isoforms including ACOX1a and ACOX1b, transcribed from a single gene. As ACOX1a shows reduced activity toward palmitoyl-CoA as compared with ACOX1b, we used adenovirally driven ACOX1a and ACOX1b to investigate their efficacy in the reversal of hepatic phenotype in Acox1(À/À) mice. In this study, we show that human ACOX1b is markedly effective in reversing the ACOX1 null phenotype in the mouse. In addition, expression of human ACOX1b was found to restore the production of nervonic (24:1) acid and had a negative impact on the recruitment of coactivators to the PPARa-response unit, which suggests that nervonic acid might well be an endogenous PPARa antagonist, with nervonoyl-CoA probably being the active form of nervonic acid. In contrast, restoration of docosahexaenoic (22:6) acid level, a retinoid-X-receptor (RXRa) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRa and coactivators to the PPARa-response unit. The human ACOX1b isoform is more effective than the ACOX1a isoform in reversing the Acox1 null phenotype in the mouse. Substrate utilization differences between the two ACOX1 isoforms may explain the reason why ACOX1b is more effective in metabolizing PPARa ligands.

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mentioning

confidence: 99%

Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

Vluggens

Andreoletti

Viswakarma

et al. 2010

Laboratory Investigation

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“…The fibroblasts from the XALD patient had impaired C26:0 ␤ -oxidation, which is caused by a mutation in the gene encoding the peroxisomal membrane protein adrenoleukodystrophy protein (ALDP) (19). The SCOX-and DBP-deficient patients all had mutations in the encoding gene, and no enzyme activity could be measured in fibroblasts of these patients (20,21). Peroxisomes from the patient with RCDP type 1 lack 3-ketoacyl-CoA thiolase as a result of a mutation in the PEX7 gene encoding the peroxisomal targeting signal 2 receptor.…”

Section: Patient Cell Linesmentioning

confidence: 99%

Identification of the peroxisomal β-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids

Ferdinandusse

Denis

Roermund

et al. 2004

Journal of Lipid Research

126

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Dicarboxylic acids (DCAs) are -oxidation products of monocarboxylic acids. After activation by a dicarboxylyl-CoA synthetase, the dicarboxylyl-CoA esters are shortened via ␤ -oxidation. Although it has been studied extensively where this ␤ -oxidation process takes place, the intracellular site of DCA oxidation has remained controversial. Making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this paper that peroxisomes, and not mitochondria, are involved in the ␤ -oxidation of C16DCA. Additional studies in fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d -bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, together with direct enzyme measurements with human recombinant l -bifunctional protein (LBP) and DBP expressed in a fox2 deletion mutant of Saccharomyces cerevisiae , show that the main enzymes involved in ␤ -oxidation of C16DCA are SCOX, both LBP and DBP, and sterol carrier protein X, possibly together with the classic 3-ketoacyl-CoA thiolase. This is the first indication of a specific function for LBP, which has remained elusive until now. -Ferdinandusse, S., S. Denis, C. W. T. van Roermund, R. J. A. Wanders, and G. Dacremont. Identification of the peroxisomal ␤ -oxidation enzymes involved in the degradation of long-chain dicarboxylic acids.

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“…There is less conservation in this Pex5p region in the other three species, Y. lipolytica, P. pastoris, and H. sapiens. In the latter two cases this may be explained by the fact that acyl-CoA oxidase in these species is targeted to peroxisomes via the classical PTS1 pathway (63,66).…”

Section: Figmentioning

confidence: 99%

Saccharomyces cerevisiae Acyl-CoA Oxidase Follows a Novel, Non-PTS1, Import Pathway into Peroxisomes That Is Dependent on Pex5p

Klein

Berg

Bottger

et al. 2002

Journal of Biological Chemistry

127

139

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The peroxisomal protein acyl-CoA oxidase (Pox1p) of Saccharomyces cerevisiae lacks either of the two well characterized peroxisomal targeting sequences known as PTS1 and PTS2. Here we demonstrate that peroxisomal import of Pox1p is nevertheless dependent on binding to Pex5p, the PTS1 import receptor. The interaction between Pex5p and Pox1p, however, involves novel contact sites in both proteins. The interaction region in Pex5p is located in a defined area of the amino-terminal part of the protein outside of the tetratricopeptide repeat domain involved in PTS1 recognition; the interaction site in Pox1p is located internally and not at the carboxyl terminus where a PTS1 is normally found. By making use of pex5 mutants that are either specifically disturbed in binding of PTS1 proteins or in binding of Pox1p, we demonstrate the existence of two independent, Pex5p-mediated import pathways into peroxisomes in yeast as follows: a classical PTS1 pathway and a novel, non-PTS1 pathway for Pox1p.

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Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy.

Cited by 72 publications

References 23 publications

Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

Identification of the peroxisomal β-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids

Saccharomyces cerevisiae Acyl-CoA Oxidase Follows a Novel, Non-PTS1, Import Pathway into Peroxisomes That Is Dependent on Pex5p

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