References of "Genin, Emmanuelle"
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See detailNeuronal Differentiation in the Adult Brain: Cdk6 as the Molecular Regulator
Caron, Nicolas ULg; Genin, Emmanuelle ULg; Vandenbosch, Renaud ULg et al

in Hayat, Eric (Ed.) TUMORS OF THE CENTRAL NERVOUS SYSTEM (2013)

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See detailIncidence of Abcd1 level on the induction of cell death and organelle dysfunctions triggered by very long chain fatty acids and TNF-alpha on oligodendrocytes and astrocytes
Baarine, Mauhamad; Ragot, Kevin; Athias, Anne et al

in NeuroToxicology (2012), 33(2)

X-linked adrenoleukodystrophy (X-ALD) is characterized by ABCD1 deficiency. This disease is associated with elevated concentrations of very long chain fatty acids (C24:0 and C26:0) in the plasma and ... [more ▼]

X-linked adrenoleukodystrophy (X-ALD) is characterized by ABCD1 deficiency. This disease is associated with elevated concentrations of very long chain fatty acids (C24:0 and C26:0) in the plasma and tissues of patients. Under its severe form, brain demyelination and inflammation are observed. Therefore, we determined the effects of C24:0 and C26:0 on glial cells:oligodendrocytes, which synthesize myelin, and astrocytes, which participate in immune response. So, 158N murine oligodendrocytes, rat C6 glioma cells, rat primary cultures of neuronal–glial cells, and of oligodendrocytes were treated for various periods of time in the absence or presence of C24:0 and C26:0 used at plasmatic concentrations found in X-ALD patients (1–5 μM) and higher (10, 20, 40 μM). To evaluate the importance of extrinsic and intrinsic factors, the part taken by TNF-α and reduced Abcd1 level was studied. Whatever the cells considered, no effects on cell growth and/or viability were detected at 1–5 μM, more or less pronounced effects were identified at 10 μM, and an induction of cell death with increased permeability to propidium iodide and loss of transmembrane mitochondrial potential was observed at 20–40 μM. On 158N, cell death was characterized by (i) an increased superoxide anion production at the mitochondrial level; (ii) the presence of vacuoles of different sizes and shapes; a destabilization of lysosomal membrane and a cytoplasmic redistribution of lysosomes; (iii) a modulation of Abcd3/PMP70 and Acox-1 protein expression, and a decrease in catalase activity at the peroxisomal level. When TNF-α was combined with C24:0 or C26:0 and used on 158N cells, C6 cells, and on 158N cells after siRNA mediated knockdown of Abcd1, no or slight potentiation was revealed. Thus, on the different cell models used, an induction of cell death with marked cellular dysfunctions at the mitochondrial, lysosomal, and peroxisomal levels were found with C24:0 and C26:0 at 20 μM and higher. However, in our experimental conditions, plasmatic concentrations of these fatty acids were unable to induce cell death, and organelle dysfunctions on oligodendrocytes and astrocytes, and additional intrinsic and environmental factors, such as reduced Abcd1 level and/or TNF-α, were ineffective to potentiate their side effects. [less ▲]

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See detailSubstrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)
Genin, Emmanuelle ULg; Geillon, Flore; Gondcaille, Catherine et al

in Journal of Biological Chemistry (2011), 286 (10)

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D ... [more ▼]

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP. ALDP is supposed to function as a homodimer allowing the entry of CoA-esters of very-long chain fatty acids (VLCFA) into the peroxisome, the unique site of their β-oxidation. ALDP deficiency can be corrected by overexpression of ALDRP, its closest homolog. However, the exact nature of the substrates transported by ALDRP and its relationships with ALDP still remain unclear. To gain insight into the function of ALDRP, we used cell models allowing the induction in a dose-dependent manner of a wild type or a mutated non-functional ALDRP-EGFP fusion protein. We explored the consequences of the changes of ALDRP expression levels on the fatty acid content (saturated, monounsaturated, and polyunsaturated fatty acids) in phospholipids as well as on the levels of β-oxidation of 3 suspected substrates: C26:0, C24:0, and C22:6n-3 (DHA). We found an inverse correlation between the fatty acid content of saturated (C26:0, C24:0) and monounsaturated (C26:1, C24:1) VLCFA and the expression level of ALDRP. Interestingly, we obtained a transdominant-negative effect of the inactive ALDRP-EGFP on ALDP function. This effect is due to a physical interaction between ALDRP and ALDP that we evidenced by proximity ligation assays and coimmunoprecipitation. Finally, the β-oxidation assays demonstrate a role of ALDRP in the metabolism of saturated VLCFA (redundant with that of ALDP) but also a specific involvement of ALDRP in the metabolism of DHA. [less ▲]

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See detailPeroxisomal and mitochondrial status of two murine oligodendrocytic cell lines (158N, 158JP): potential models for the study of peroxisomal disorders associated with dysmyelination processes
Baarine, Mauhamad; Ragot, Kevin; Genin, Emmanuelle ULg et al

in Journal of Neurochemistry (2009), 111

In some neurodegenerative disorders (leukodystrophies) characterized by myelin alterations, the defect of peroxisomal functions on myelin-producing cells (oligodendrocytes) are poorly understood. The ... [more ▼]

In some neurodegenerative disorders (leukodystrophies) characterized by myelin alterations, the defect of peroxisomal functions on myelin-producing cells (oligodendrocytes) are poorly understood. The development of in vitro models is fundamental to understanding the physiopathogenesis of these diseases. We characterized two immortalized murine oligodendrocyte cell lines: a normal (158N) and a jimpy (158JP) cell line mutated for the proteolipid protein PLP/DM20. Fluorescence microscopy, flow cytometry, and western blotting analysis allow to identify major myelin proteins (PLP colocalizing with mitochondria; myelin basic protein), oligodendrocyte (CNPase and myelin oligodendrocyte glycoprotein), and peroxisomal markers [adrenoleukodystrophy protein, PMP70, acyl-CoA oxidase 1 (ACOX1), l-peroxisomal bifunctional enzyme, and catalase]. Using electron microscopy, peroxisomes were identified in the two cell lines. Gene expression (ATP-binding cassette, Abcd1, Abcd2, Abcd3, and Acox1) involved in peroxisomal transport or beta-oxidation of fatty acids was evaluated using quantitative PCR. 4-phenylbutyrate treatment increases expression of ACOX1, l-peroxisomal bifunctional enzyme, PLP, myelin oligodendrocyte glycoprotein, and CNPase, mainly in 158N cells. In both cell lines, 4-phenylbutyrate-induced ACOX1 and catalase activities while only Abcd2 gene was up-regulated in 158JP. Moreover, the higher mitochondrial activity and content observed in 158JP were associated with higher glutathione content and increased basal production of reactive oxygen species revealing different redox statuses. Altogether, 158N and 158JP cells will permit studying the relationships between peroxisomal defects, mitochondrial activity, and oligodendrocyte functions. [less ▲]

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See detailInduction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics
Genin, Emmanuelle ULg; Gondcaille, Catherine; Trompier, Doriane et al

in Journal of Steroid Biochemistry & Molecular Biology (2009), 116 (1-2)

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 (ALD) gene. The ABCD2 gene, its closest homolog, has been shown to compensate for ABCD1 deficiency when ... [more ▼]

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 (ALD) gene. The ABCD2 gene, its closest homolog, has been shown to compensate for ABCD1 deficiency when overexpressed. We previously demonstrated that the ABCD2 promoter contains a functional thyroid hormone response element. Thyroid hormone (T3) through its receptor TRbeta can induce hepatic Abcd2 expression in rodents and transiently normalize the VLCFA level in fibroblasts of Abcd1 null mice. In a therapeutic perspective, the use of selective agonists of TRbeta should present the advantage to be devoid of side effects, at least concerning the cardiotoxicity associated to TRalpha activation. In this study, we compared the effects of T3 with those of two thyromimetics (GC-1 and CGS 23425) specific of TRbeta. Using a gene reporter assay, we demonstrated that the rat Abcd2 promoter responds to the thyromimetics in a dose-dependent way similar to what is observed with T3. We then investigated the effects of 2-, 4- and 10-day treatments on the expression of ABCD2 and its paralogs ABCD3 and ABCD4 in human cell lines by RT-qPCR. Both thyromimetics trigger up-regulation of ABCD2-4 genes in HepG2 cells and X-ALD fibroblasts. Interestingly, in X-ALD fibroblasts, while T3 is associated with a transient induction of ABCD2 and ABCD3, the treatments with thyromimetics allow the induction to be maintained until 10 days. Further in vivo experiments in Abcd1 null mice with these thyromimetics should confirm the therapeutic potentialities of these molecules. [less ▲]

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