Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics

Génin, Emmanuelle; Gondcaille, Catherine; Trompier, Doriane; Savary, Stéphane

doi:10.1016/j.jsbmb.2009.04.006

Cited by 32 publications

(17 citation statements)

References 47 publications

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“…cDNA was generated using Moloney murine leukemia virus reverse transcriptase enzyme (Promega). Quantification of cDNA expression was carried out using the SYBR Green real time PCR technology and an iCycler iQ Real Time Detection System (Bio-Rad) as previously described (24). The primers 5Ј-GGCATCACCA-CTAAAATCTCC-3Ј (rat 36b4 forward), 5Ј-GCTCCCACC-TTGTCTCCA-3Ј (rat 36b4 reverse), 5Ј-CAGCGTCCACC-TCTACCACATAG-3Ј (rat Abcd2 forward), and 5Ј-CGTC-CAGCAATGCGTACTTCG-3Ј (rat Abcd2 reverse) were chosen using the Beacon Designer Software (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Génin

Geillon

Gondcaille

et al. 2011

Journal of Biological Chemistry

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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 ␤-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 ␤-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 ␤-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. X-linked adrenoleukodystrophy (X-ALD)2 (OMIM 300100) is a very complex neurodegenerative disorder whose physiopathogenesis remains to be clarified (1). X-ALD is caused by mutations in the ABCD1 gene located in Xq28, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP (adrenoleukodystrophy-protein) (2). This protein has the structure of a half ABC transporter, which is supposed to function as a homodimer (3, 4). However, heterodimerization with one of the other members of the ABCD subfamily (i.e. ALDRP (encoded by the ABCD2 gene (5)), PMP70 (ABCD3 (6)), and PMP69 (ABCD4 (7, 8)) cannot be excluded especially in the situation where these proteins are overexpressed. Although a mirror expression pattern is often observed between ALDP and ALDRP when specific cell types are analyzed (9), peroxisomal ABC transporters have overlapping expression patterns rendering possible such interactions (5, 10). Coimmunoprecipitation experiments or FRET analysis have demonstrated heterodimerization in cells overexpressing the peroxisomal ABC transporters (11,12). Although the peroxisomal localization of ALDP, ALDRP, and PMP70 is clearly demonstrated, PMP69 has recently been described to be localized in the endoplasmic reticulum and was found to be absent in the peroxisome. This excludes a possible interaction at the peroxisomal membrane with the other ABC...

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Section: Methodsmentioning

confidence: 99%

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Génin

Geillon

Gondcaille

et al. 2011

Journal of Biological Chemistry

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“…and ABCD3 genes were found stably up-regulated in human HepG2 and X-ALD skin fibroblasts treated with two thyromimetics GC-1 or CGS23425, serving as the proof of concept of a possible indication for X-ALD [478]. Further studies, particularly in animals, are however needed to confirm the therapeutic potentialities of these molecules.…”

Section: Therapeutic Strategies 65mentioning

confidence: 96%

X-linked Adrenoleukodystrophy

Trompier¹,

Savary²

2013

Colloquium Series on the Genetic Basis of Human Disease

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“…11 In terms of potential for CNS disorders, sobetirome has been studied in pre-clinical models of X-linked adrenoleukodystrophy (X-ALD), a lipid storage disease that produces severe neurological phenotypes involving demyelination. 12 In addition, sobetirome has been shown to promote oligodendrogenesis from human and rodent OPCs in vitro , and enhance oligodendrogenesis during development with attending increased production of myelin proteins in vivo , supporting the idea that thyromimetic agents that distribute to the central nervous system (CNS) may be useful candidates for treating demyelinating disorders. 13 …”

Section: Introductionmentioning

confidence: 95%

Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration

Ferrara

Meinig

Placzek

et al. 2017

Bioorganic & Medicinal Chemistry

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Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.

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Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics

Cited by 32 publications

References 47 publications

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

X-linked Adrenoleukodystrophy

Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration

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