| Human Molecular Genetics | Pages |
Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy
Introduction
Results
Expression of ALDP and ALDRP leads to restoration of VLCFA [beta]-oxidation in X-ALD fibroblasts
Normalization of VLCFA content by stable expression of ALDRP in X-ALD fibroblasts
Restoration of [beta]-oxidation is not due to stabilization of ALDP in ALDR-expressing fibroblasts
Restoration of peroxisomal [beta]-oxidation in the liver of fenofibrate-treated mice
Discussion
Materials And Methods
Cell lines and cell culture
Plasmids
Transfection
Identification of transfected clones by PCR
Antibodies and immunofluorescence detection
[beta]-Oxidation assay
Gas chromatographic analysis of VLCFAs
Fenofibrate treatment of mice
Northern blot analysis
Western blot analysis
Abbreviations
Acknowledgements
References
Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy
INTRODUCTION
X-linked adrenoleukodystrophy (X-ALD; McKusick 300100) is a peroxisomal neurodegenerative disease with widely varying clinical phenotypes, ranging from the severe childhood cerebral form with progressive inflammatory demyelination in the brain to the mildest form, Addison-only, characterized by adrenocortical insufficiency as the only clinical symptom (for reviews, see refs 1,2). To date, the only treatment with some benefits for patients with the neurodegenerative variants of the disease appears to be bone marrow transplantation carried out at early stages of the disease. The disorder is characterized by the accumulation of saturated, unbranched very long chain fatty acids (VLCFAs; [ge]C22:0) in plasma, tissues and cultured fibroblasts, which is due to impaired VLCFA [beta]-oxidation. The defective step in the peroxisomal [beta]-oxidation is associated with the initial activation of VLCFAs catalyzed by very long chain acyl-CoA synthetase (3-6). However, the ALD gene identified by positional cloning (7) does not encode this enzyme, but a gene product belonging to a family of transmembrane proteins, the ATP-binding cassette (ABC) transporters (8-10). In all patients studied, mutations were found in the ALD gene, and ~70% of patients lack immunoreactive adrenoleukodystrophy protein (ALDP). In cultured fibroblasts from X-ALD patients, [beta]-oxidation can be restored by transfection with normal ALD cDNA (11,12), indicating that the mutant ALDP is indeed the cause of impaired [beta]-oxidation. The exact function of ALDP and its relationship to the acyl-CoA synthetase still remain unclear.
ABC transporters have a wide range of substrates and consist of two hydrophobic transmembrane domains and two hydrophilic nucleotide-binding folds (13). The ALD protein structurally represents a half-transporter, with only one of each of these domains, and presumably has to form a homo- or heterodimer to become a functional unit. Three other mammalian half-ABC transporters, structurally similar to ALDP, have been identified: the ALD-related protein [ALDRP (14)], the 70 kDa peroxisomal membrane protein [PMP70 (15)] and the PMP70-related protein [P70R (16,17)], with 63, 33 and 25% amino acid identity to ALDP, respectively. However, these genes show differing expression patterns (14,18-20).
It was reported recently that transient overexpression of PMP70 and ALDR cDNAs leads to restoration of VLCFA [beta]-oxidation in cultured human X-ALD fibroblasts (21,22). This was unexpected for PMP70, since X-ALD fibroblasts endogenously express PMP70. Apparently, overexpression is required to suppress the [beta]-oxidation defect. In contrast, expression of ALDRP, the closest relative of ALDP, is normally not detectable in human fibroblasts. Here we demonstrate that, as previously shown in transient overexpression (22), ALDRP can also restore peroxisomal [beta]-oxidation efficiently in stably transformed X-ALD fibroblasts and, in addition, prevent VLCFA accumulation. Furthermore, VLCFA [beta]-oxidation could be restored in the liver of ALDP-deficient mice after fenofibrate stimulation of ALDR and PMP70 gene expression.
RESULTS
Expression of ALDP and ALDRP leads to restoration of VLCFA [beta]-oxidation in X-ALD fibroblasts
Normally, fibroblasts do not express ALDR protein or mRNA. To investigate the influence of expression of ALDP and ALDRP on [beta]-oxidation in an ALDP/ALDRP-deficient system, we used SV40-transformed skin fibroblasts from an X-ALD patient with the missense mutation A626T, which lack the punctate immunoreactive staining pattern characteristic for ALDP (23). Expression plasmids were constructed containing the human ALD and ALDR cDNA, respectively, under control of the cytomegalovirus (CMV) promoter. Since the subcellular localization of ALDRP has only been shown for the mouse protein (24), a haemagglutinin (HA) tag was added to the C-terminus of one ALDRP expression construct. Indirect immunofluorescence demonstrated a peroxisomal localization of the ALDR-HA protein in transfected fibroblasts (data not shown), indicating that the ALDR construct is expressed and localized correctly. As controls for unspecific stimulation of peroxisomal [beta]-oxidation, the expression vector alone (pcDNA3.1), the vector expressing chloramphenicol acetyltransferase (pcDNA3.1/CAT), and pEGFP-C3, a vector expressing green fluorescent protein (GFP) under the control of the CMV promoter, were used. GFP was selected as it should not influence [beta]-oxidation, and transfection efficiency can be established easily. The mean transfection efficiency was estimated to be ~20% (15-33%; data not shown) for the constructs expressing ALDP, ALDRP-HA and GFP.
The ratio of [beta]-oxidation of lignoceric acid (C24:0) versus palmitic acid (C16:0) was determined in extracts from transformed normal and X-ALD fibroblasts, showing that [beta]-oxidation of VLCFAs was decreased in ALDP-deficient fibroblasts to ~25% of the control (Fig.
Figure 1. [beta]-Oxidation activity (C24:0/C16:0) in control and X-ALD fibroblasts. X-ALD fibroblasts were transiently transfected with cDNA encoding wild-type ALDP (ALD), ALDRP (ALDR) or pcDNA3.1 (vector). Values are means ± SD for n = 6.
Normalization of VLCFA content by stable expression of ALDRP in X-ALD fibroblasts
X-ALD fibroblasts accumulate ~10-fold amounts of C26:0 fatty acid in comparison with healthy controls. To investigate whether this accumulation can be suppressed by expression of ALDRP, we generated fibroblasts stably expressing ALDRP. RNA was isolated from individual clones for northern blot analysis, and strong expression of ALDR could be shown in a stable clone, whereas no ALDR mRNA expression was detectable in control or in X-ALD fibroblasts (Fig.
Figure 2. Analysis of X-ALD fibroblasts stably expressing ALDRP (+).(a) Northern blot analysis of ALDR and PMP70 mRNA expression. [beta]-Actin is shown as a control of equal loading and transfer. (b) [beta]-Oxidation activity (C24:0/C16:0). Values are means ± SD for n = 6 (control and X-ALD fibroblasts without ALDR expression) and n = 3 (X-ALD fibroblasts expressing ALDR). (c) Accumulation of VLCFAs in fibroblasts presented as the ratio of C26:0/C22:0 fatty acids. VLCFA content was determined by gas chromatography. [beta]-Oxidation was determined in control, X-ALD and stably transfected fibroblasts. VLCFA [beta]-oxidation was increased more strongly in the ALDRP-expressing clone than in the transiently transfected fibroblasts, leading to a value ~2-fold higher than in healthy control fibroblasts (Fig. After 2 months of growth, the VLCFA content of X-ALD cells stably expressing ALDRP was determined by gas chromatography. VLCFA levels were now normalized (Fig. 
Restoration of [beta]-oxidation is not due to stabilization of ALDP in ALDR-expressing fibroblasts
In yeast, only two peroxisomal half-ABC transporters, Pxa1p and Pxa2p, are known (25,26). These form a heterodimer, and the absence of Pxa2p leads to destabilization of Pxa1p (27). Thus, a possible mechanism for restoration of [beta]-oxidation by ALDR protein in human X-ALD fibroblasts could be via stabilization of the mutant, unstable, but possibly functional ALD protein. However, by indirect immunofluorescence, using an anti-ALDP antibody, no ALDP was detectable in cells transfected with ALDRP (data not shown). These results suggest that the ALDR protein itself is able functionally to replace the missing ALD protein.
Restoration of peroxisomal [beta]-oxidation in the liver of fenofibrate-treated mice
Dietary treatment with the peroxisome proliferator fenofibrate leads to up-regulation of ALDR and PMP70 gene expression in the liver of rodents (28), and both PMP70 (21) and ALDRP (22) are able to restore [beta]-oxidation upon overexpression in X-ALD fibroblasts. Since ALDP-deficient mice show VLCFA accumulation in many tissues, including the liver (29), it is possible to investigate whether fenofibrate treatment can restore [beta]-oxidation also in vivo. Wild-type and ALDP-deficient mice (30) were fed a diet supplemented with 0.3% fenofibrate. After 7 days of treatment, the livers of control and fenofibrate-treated mice were dissected, RNA and protein were isolated for northern and western blot analyses, respectively, and the rate of lignoceric acid [beta]-oxidation was determined. Northern blot analysis of ALDR and PMP70 mRNA expression showed that fenofibrate stimulated expression of both genes in the liver of wild-type as well as ALDP-deficient mice (Fig.
Figure 3. Effect of fenofibrate on gene expression and [beta]-oxidation in mouse liver. (a) Northern blot analysis of ALDR and PMP70 mRNA expression in the liver of wild-type and ALDP-deficient mice. Approximately 2 µg of poly(A)+ RNA each from control (-) and fenofibrate-treated mice (+) were analyzed by northern blotting. [beta]-Actin was used as a control of equal loading and transfer. (b) C24:0 [beta]-oxidation activity in the liver of wild-type and ALDP-deficient control (-) and fenofibrate-treated (+) mice. Values are means ± SD for n = 3. In the liver of the ALDP-deficient mice on a regular diet, lignoceric acid [beta]-oxidation was reduced to ~50% of the value in wild-type mice (Fig. 
DISCUSSION
The high degree of amino acid identity between the closest relatives ALDRP and ALDP already suggested functional similarity, and here we could show that expression of ALDRP in X-ALD fibroblasts lacking detectable ALD protein leads to restoration of [beta]-oxidation and-in clones stably overexpressing ALDRP-to normalization of the VLCFA concentration. In contrast to a recently published study (22) reporting a normalized peroxisomal [beta]-oxidation activity in transiently ALDR-transfected X-ALD fibroblasts only after correcting for transfection efficiency, we achieved a level similar to that of the healthy control without correcting for transfection efficiency in the transient study. The apparently more efficient restoration in our study may be due to differences in the ALDR expression constructs or transfection procedure. As expected, the [beta]-oxidation rate was even higher (twice the control) in our stable ALDR-expressing clone. This suggests that, at least in normal fibroblasts, ALDP may be a rate-limiting factor for VLCFA [beta]-oxidation.
By indirect immunofluorescence, it could be excluded that the effect of ALDRP leading to restoration of [beta]-oxidation in X-ALD fibroblasts was due to stabilization of mutant ALDP. These data strongly indicate that ALDRP itself is able to replace ALDP functionally.
To evaluate whether overexpression of peroxisomal ABC proteins other than ALDP could correct [beta]-oxidation also in vivo, expression of ALDR and PMP70 was stimulated in the liver of mice. ALDP-deficient mice recapitulate the biochemical defects of X-ALD, i.e. the accumulation of VLCFAs in various tissues and impaired [beta]-oxidation of VLCFAs in fibroblasts and hepatocytes (29-31). The peroxisome proliferator fenofibrate, a frequently used hypolipidemic drug without severe side effects, recently has been shown to stimulate ALDR and PMP70 expression in the liver of rats (28). Treatment of wild-type and ALDP-deficient mice with fenofibrate also results in strong stimulation of ALDR and PMP70 gene expression in the liver. This overexpression did not exhibit any significant effect on [beta]-oxidation in the wild-type mice. In the liver of ALDP-deficient mice, VLCFA [beta]-oxidation was normalized after fenofibrate treatment. These results indicate that ALDR and/or PMP70 can take over the function of deficient ALDP in X-ALD. In addition to ALDP and ALDRP stimulation, fenofibrate may exert pleiotropic effects on other enzymes, including very long-chain acyl-CoA synthetase, that could also affect [beta]-oxidation of VLCFAs. Redundant function of ALDP and ALDRP is suggested not only by the structural similarity, but also by the complementary expression patterns of ALD and ALDR in mouse tissues and human cell lines (20). Cell types with little or no detectable ALDP often express high levels of ALDRP, indicating that one of these proteins is necessary and sufficient for normal cell function. This could be the reason why ALDRP is unable to compensate for the loss of ALDP in X-ALD patients. However, the phenotypic heterogeneity of the disease could be related to a constitutive or induced change in ALDR or PMP70 gene expression. Additional stimulation of ALDR and/or PMP70 expression, especially in cell types which normally do not express these genes, appears to be a feasible approach for the development of a new therapy for X-ALD.
Fenofibrate stimulates PMP70 and ALDR expression mainly in the liver of rodents (28), and presumably it would be necessary to induce overexpression of at least one of these genes in all crucial cell types of the affected tissues, in particular in brain and adrenals. The mechanism that leads to this stimulation by fenofibrate has not yet been identified, but activation of transcription via peroxisome proliferator-activated receptor (PPAR) and retinoic acid receptor has been suggested (20). One reason why fenofibrate is not effective in the brain could be a lack of the particular PPAR subtype necessary for activation in brain. However, it has been shown that PPAR[alpha] and [beta] are ubiquitously expressed in rat brain (32,33), and fenofibrate presumably activates PPAR[alpha] (34). Therefore, it appears more likely that fenofibrate would, in principle, have an effect in brain, but is not able to cross the blood-brain barrier. In this case, it might be possible to find some way to mediate penetration of fenofibrate or a similarly acting substance into the brain. Several drugs, such as 4-phenylbutyrate (22), lovastatin and sodium phenylacetate (35), or compounds increasing the cAMP level (36), have been shown to normalize VLCFAs in skin fibroblasts of X-ALD patients. In the case of 4-phenylbutyrate, this seems to be accomplished by a stimulation of ALDRP expression in addition to peroxisome proliferation (22), whereas for the other drugs the mechanisms underlying the functional rescue require more detailed investigation. It can be anticipated that pharmaceutical correction of the biochemical defect in X-ALD can be achieved via a single drug (4-phenylbutyrate, lovastatin or fenofibrate) or via a combination of different drugs. However, it is necessary to evaluate further whether the correction of the VLCFA metabolism will influence the neurodegenerative course of the disease, as there currently is no proof that the accumulation of VLCFAs per se is the cause of the neurological symptoms.
MATERIALS AND METHODS
Cell lines and cell culture
SV40-transformed skin fibroblasts from an X-ALD patient lacking detectable ALD protein were kindly provided by Dr K.D. Smith and Dr L.T. Braiterman (Baltimore, MD; patient no. 11 with mutation A626T in ref. 23). Control fibroblasts were obtained from skin biopsies of probands without metabolic diseases and were transformed using the plasmids pSVBam and pEJ6.6 (37) containing the entire SV40 genome and activated Ha-RAS, respectively, in pBR322. Cells were maintained in RPMI 1640 medium (Biowhittaker, Walkersville, MD) supplemented with 2 mM l-glutamine (Biowhittaker), 10% (v/v) inactivated fetal calf serum (Serva, Heidelberg, Germany) and 50 U/ml penicillin/streptomycin (Biowhittaker).
Plasmids
The entire coding regions of the human ALD (7) and ALDR (16) cDNAs, respectively, were EcoRI-inserted into the eukaryotic expression vector pcDNA3.1 (+) (Invitrogen, Groningen, The Netherlands). An HA tag was added to the 3[prime] end of the ALDR cDNA by PCR using an upstream oligonucleotide primer corresponding to the translational start (nucleotide 136 of the ALDR cDNA; EMBL accession no. AJ000327) and the following downstream primer: 5[prime]-gctctagattactaagcgtagtctgggacgtcgtatgggtaagatgtctcatcttcatttttaattg-3[prime]. The HA tag-introducing PCR primer consists of a part complementary to the 3[prime] end of the ALDRP-coding sequence followed by the nucleotides introducing the nine amino acids of the HA epitope (YPYDVPDYA), two stop codons and a recognition site for the restriction enzyme XbaI. The PCR product was ligated into the ALDR expression vector and the resulting construct was sequenced. As controls, the vector alone, pcDNA3.1(+)/CAT (Invitrogen), and an expression vector for GFP, pEGFP-C3 (Clontech, Palo Alto, CA), were used.
Transfection
SV40-transformed fibroblasts were transfected with plasmid DNA by electroporation. About 5 × 106 cells were suspended in 0.5 ml of normal growth medium, 20 µg of plasmid DNA was added, and the suspension was subjected to an electric pulse of 200 V at a capacitance of 950 µF using the Gene Pulser II and Capacitance Extender PLUS (Bio-Rad, Hercules, CA). For transient transfection, electroporated cells were grown for 4 days prior to analysis.
To obtain stable cell lines, transfected cells were subjected to selection by G418 (Serva) at 200 µg/ml medium starting 2 days after transfection, and individual clones were isolated and expanded after 2 weeks of selection.
Identification of transfected clones by PCR
After 4 weeks of selection, DNA was isolated for identification of clones with stably integrated ALDR cDNA. The cells were grown to confluency in 24-well plates, washed twice with phosphate-buffered saline (PBS; Biowhittaker) and incubated in lysis buffer (10 mM Tris, pH 7.7, 10 mM EDTA, 10 mM NaCl, 0.5% sarcosyl, 1 mg/ml proteinase K) at 60°C overnight. DNA was precipitated with a mixture of NaCl and ethanol (150 µl of 5 M NaCl in 10 ml of cold ethanol), resuspended in TE buffer (10 mM Tris, 1 mM EDTA) and used for PCR. The oligonucleotide primers for amplification of ALDR cDNA were Oli 210 (nucleotides 177-199 of EMBL accession no. AJ000327) and Oli 214 (nucleotides 1975-1994 of EMBL accession no. AJ000327), leading to amplification of an 1818 bp fragment only in clones containing the integrated ALDR cDNA constructs. The endogenous ALDR gene contains introns between these two primers and, therefore, the genomic fragment is too large for amplification under the conditions used.
Antibodies and immunofluorescence detection
Indirect immunofluorescence studies of fibroblasts were performed as described elsewhere (38). Aliquots of the transfected cells were plated on glass coverslips immediately after transfection and analyzed by immunofluorescence 4 days later with the following commercially available antibodies: mouse monoclonal anti-ALDP antibody (ALD-1D6, dilution 1:500; Euromedex, Souffelweyersheim, France), mouse monoclonal anti-HA antibody (1:40; Boehringer Mannheim, Mannheim, Germany), sheep anti-human catalase antibody (1:100; The Binding Site, Birmingham, UK), biotinylated anti-mouse antibody (1:200; Amersham, Little Chalfont, UK), FluoroLink Cy2 Avidin (1:50; Amersham) and rhodamine-conjugated anti-sheep antibody (1:100; Accurate Chemical and Scientific, Westbury, NY). GFP was visualized by direct exposure to blue light. Co-localization with catalase was confirmed by simultaneous incubation with anti-catalase and anti-ALDP or anti-HA antibodies and comparison of the staining pattern. Transfection efficiency was determined by counting immunostained and non-stained cells in 10 visual fields at 400× magnification.
[beta]-Oxidation assay
The rate of [beta]-oxidation in fibroblasts and freshly dissected or frozen mouse liver was determined in duplicate as described elsewhere (39). In separate reactions, 1-2 × 105 d.p.m. of [1-14C]lignoceric acid (C24:0) and [1-14C]palmitic acid (C16:0) (both obtained from American Radiolabeled Chemicals, St Louis, MO) were brought to 5 nmol with the respective unlabeled fatty acid and added to fibroblast and mouse liver extracts. After 1 h incubation at 37°C, the amount of degraded fatty acids was determined by measuring the release of water-soluble radioactivity. The [beta]-oxidation activity was calculated as nmol/h/mg protein, and the C24:0/C16:0 ratio was determined.
Gas chromatographic analysis of VLCFAs
For VLCFA determination, a confluent 75 cm2 flask of each cell type was harvested by trypsinization. The cell pellet was dispersed in 0.5-1.0 ml of distilled water, sonicated for 30 s at 70 W efficiency, and the protein content determined. As an internal standard, 2.5 µg of C23:0 fatty acid in 50 µl was added with 5 ml of chloroform/methanol (1:1) to 0.5 ml of fibroblast homogenate (500 µg-2 mg of protein) and kept at room temperature for 1 h. The protein precipitate was removed by centrifugation and Folch partition was performed (40). Fatty acid methyl esters were prepared according to `procedure 1' for plasma samples (41), and analyzed by gas chromatography as previously described (30).
Fenofibrate treatment of mice
Three-month-old ALDP-deficient male mice and wild-type littermates on a C57BL/6×129 hybrid background (30) were fed a normal diet supplemented with 0.3% fenofibrate for 1 week. Pellets were soaked with fenofibrate (Sigma, St Louis, MO) dissolved in acetone, which was allowed to evaporate overnight at room temperature. Fenofibrate-treated and control groups of wild-type and ALDP-deficient mice each consisted of three animals.
Northern blot analysis
Frozen mouse liver was homogenized by grinding in liquid nitrogen, and total cellular RNA was isolated using TriPure Isolation Reagent (Boehringer Mannheim) according to the manufacturer's instructions. From fresh fibroblasts, total RNA was isolated with RNeasy Mini kit (Qiagen, Hilden, Germany) as described by the manufacturer. The poly(A)+ RNA fraction was oligo(dT)-selected from 120 µg of total RNA samples using oligo(dT)-cellulose (Boehringer Mannheim) or Dynabeads (Dynal, Oslo, Norway). Poly(A)+ RNA and a size marker (RNA ladder; Gibco BRL, Paisley, UK) were fractionated on 1.2% agarose-formaldehyde gels (42) and transferred to Biodyne B nylon membranes (Pall, Portsmouth, UK). Probes were radioactively labeled by random priming using [[alpha]-32P]dCTP (Amersham). As a control of equal loading and transfer, the blots were probed with the mouse cDNA of the ubiquitously expressed [beta]-actin mRNA. For mouse liver, a 1049 bp ALDR cDNA fragment (nucleotides 31-1089 of EMBL accession no. Z48570) was used to detect ALDR mRNA. As an mPMP70-specific probe, a 697 bp cDNA fragment (nucleotides 1015-1711 of GenBank accession no. M81182) was used. RNA from human fibroblasts was probed with an 1818 bp hALDR cDNA fragment (nucleotides 172-1989 of EMBL accession no. AJ000327) and a 1980 bp hPMP70 cDNA fragment (nucleotides 25-2004 of EMBL accession no. X58528). The blots were washed to high stringency (68°C, 0.2× SSC/0.1% SDS) before autoradiographic exposure to Biomax or X-OMAT AR (Kodak, Rochester, NY) film and intensifying screens.
Western blot analysis
Fresh or frozen mouse liver was homogenized and total membranes were isolated by sodium carbonate precipitation and subsequent high speed centrifugation (43). Gel electrophoresis and western blot analysis of the membrane protein fraction was performed with the PhastSystem (Pharmacia, Uppsala, Sweden) according to the manufacturer's instructions. The membranes were incubated with rabbit anti-human PMP70 antibody kindly provided by Dr J. Gärtner (Düsseldorf), with biotinylated anti-rabbit antibody (1:400; Amersham) and with avidin-peroxidase (1:400; Sigma). For visualization, ECL detection reagents and Hyperfilm (Amersham) were used as described by the manufacturer.
ABBREVIATIONS
ABC, ATP-binding cassette; ALDP, adrenoleukodystophy protein; ALDRP, adrenoleukodystrophy-related protein; HA, haemagglutinin; PMP70, 70 kDa peroxisomal membrane protein; VLCFA, very long-chain fatty acid; X-ALD, X-linked adrenoleukodystrophy.
ACKNOWLEDGEMENTS
We thank C. Truppe for excellent technical assistance, and K.D. Smith and L.T. Braiterman (Baltimore, MD) for the gift of SV40-tranformed skin fibroblasts from an X-ALD patient. We also thank J. Gärtner (Düsseldorf) for providing the anti-PMP70 antibody, and A. Amsterdam (Rehovot) for the plasmids pSVBam and pEJ6.6. This work was supported by the Austrian Science Foundation, project no. P12073-MED, a grant from the Deutsche Forschungsgemeinschaft, project no. RO 727/2-1, and BIOMED 2 BMH4-CT96-1621.
REFERENCES
This article has been cited by other articles:
This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: jnl.info{at}oup.co.uk
Last modification: 8 Apr 1999
Copyright©Oxford University Press, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
J. Singh, M. Khan, and I. Singh
Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy
J. Lipid Res.,
January 1, 2009;
50(1):
135 - 147.
[Abstract]
[Full Text]
[PDF]
S. Fourcade, M. Ruiz, C. Camps, A. Schluter, S. M. Houten, P. A. W. Mooyer, T. Pampols, G. Dacremont, R. J. A. Wanders, M. Giros, et al.
A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis
Am J Physiol Endocrinol Metab,
January 1, 2009;
296(1):
E211 - E221.
[Abstract]
[Full Text]
[PDF]
S. Wiese, T. Gronemeyer, R. Ofman, M. Kunze, C. P. Grou, J. A. Almeida, M. Eisenacher, C. Stephan, H. Hayen, L. Schollenberger, et al.
Proteomics Characterization of Mouse Kidney Peroxisomes by Tandem Mass Spectrometry and Protein Correlation Profiling
Mol. Cell. Proteomics,
December 1, 2007;
6(12):
2045 - 2057.
[Abstract]
[Full Text]
[PDF]
M. Y. Golovko and E. J. Murphy
Uptake and metabolism of plasma-derived erucic acid by rat brain
J. Lipid Res.,
June 1, 2006;
47(6):
1289 - 1297.
[Abstract]
[Full Text]
[PDF]
I. Weinhofer, M. Kunze, H. Rampler, A. L. Bookout, S. Forss-Petter, and J. Berger
Liver X Receptor {alpha} Interferes with SREBP1c-mediated Abcd2 Expression: NOVEL CROSS-TALK IN GENE REGULATION
J. Biol. Chem.,
December 16, 2005;
280(50):
41243 - 41251.
[Abstract]
[Full Text]
[PDF]
I. Ferrer, J. P. Kapfhammer, C. Hindelang, S. Kemp, N. Troffer-Charlier, V. Broccoli, N. Callyzot, P. Mooyer, J. Selhorst, P. Vreken, et al.
Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage
Hum. Mol. Genet.,
December 1, 2005;
14(23):
3565 - 3577.
[Abstract]
[Full Text]
[PDF]
M. Asheuer, I. Bieche, I. Laurendeau, A. Moser, B. Hainque, M. Vidaud, and P. Aubourg
Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy
Hum. Mol. Genet.,
May 15, 2005;
14(10):
1293 - 1303.
[Abstract]
[Full Text]
[PDF]
C. Gondcaille, M. Depreter, S. Fourcade, M. R. Lecca, S. Leclercq, P. G.P. Martin, T. Pineau, F. Cadepond, M. ElEtr, N. Bertrand, et al.
Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator
J. Cell Biol.,
April 11, 2005;
169(1):
93 - 104.
[Abstract]
[Full Text]
[PDF]
A. Pujol, I. Ferrer, C. Camps, E. Metzger, C. Hindelang, N. Callizot, M. Ruiz, T. Pampols, M. Giros, and J. L. Mandel
Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy
Hum. Mol. Genet.,
December 1, 2004;
13(23):
2997 - 3006.
[Abstract]
[Full Text]
[PDF]
S. Fourcade, S. Savary, C. Gondcaille, J. Berger, A. Netik, F. Cadepond, M. El Etr, B. Molzer, and M. Bugaut
Thyroid Hormone Induction of the Adrenoleukodystrophy-Related Gene (ABCD2)
Mol. Pharmacol.,
June 1, 2003;
63(6):
1296 - 1303.
[Abstract]
[Full Text]
[PDF]
M. C. McGuinness, J.-F. Lu, H.-P. Zhang, G.-X. Dong, A. K. Heinzer, P. A. Watkins, J. Powers, and K. D. Smith
Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy
Mol. Cell. Biol.,
January 15, 2003;
23(2):
744 - 753.
[Abstract]
[Full Text]
[PDF]
I. Weinhofer, S. Forss-Petter, M. Zigman, and J. Berger
Cholesterol regulates ABCD2 expression: implications for the therapy of X-linked adrenoleukodystrophy
Hum. Mol. Genet.,
October 15, 2002;
11(22):
2701 - 2708.
[Abstract]
[Full Text]
[PDF]
A. K. Heinzer, S. Kemp, J.-F. Lu, P. A. Watkins, and K. D. Smith
Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy
J. Biol. Chem.,
August 2, 2002;
277(32):
28765 - 28773.
[Abstract]
[Full Text]
[PDF]
S. Ten, M. New, and N. Maclaren
Addison's Disease 2001
J. Clin. Endocrinol. Metab.,
July 1, 2001;
86(7):
2909 - 2922.
[Abstract]
[Full Text]
[PDF]
G. Unterrainer, B. Molzer, S. Forss-Petter, and J. Berger
Co-expression of mutated and normal adrenoleukodystrophy protein reduces protein function: implications for gene therapy of X-linked adrenoleukodystrophy
Hum. Mol. Genet.,
November 1, 2000;
9(18):
2609 - 2616.
[Abstract]
[Full Text]
[PDF]
L. X. Liu, K. Janvier, V. Berteaux-Lecellier, N. Cartier, R. Benarous, and P. Aubourg
Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters
J. Biol. Chem.,
November 12, 1999;
274(46):
32738 - 32743.
[Abstract]
[Full Text]
[PDF]
This Article 
Abstract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (62)
Request Permissions Google Scholar
Articles by Netik, A.
Articles by Berger, J.
Search for Related Content
PubMed
PubMed Citation
Articles by Netik, A.
Articles by Berger, J.
Social Bookmarking
What's this?