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Thyroid Hormone Induction of the Adrenoleukodystrophy-Related Gene (ABCD2)

Laboratoire de Biologie Moléculaire et Cellulaire, Université de Bourgogne, Dijon, France (S.F., S.S., C.G., M.B.); Brain Research Institute (J.B., A.N.) and Institute of Neurology (B.M.), University of Vienna, Vienna, Austria; and Institut National de la Santé et de la Recherche Médicale U488, Le Kremlin-Bicêtre, France (F.C., M.E.E.)

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disorder associated with impaired very-long-chain fatty-acid (VLCFA) -oxidation caused by mutations in the ABCD1 (ALD) gene that encodes a peroxisomal membrane ABC transporter. ABCD2 (ALDR) displays partial functional redundancy because when overexpressed, it is able to correct the X-ALD biochemical phenotype. The ABCD2 promoter contains a putative thyroid hormone-response element conserved in rodents and humans. In this report, we demonstrate that the element is capable of binding retinoid X receptor and 3,5,3'-tri-iodothyronine (T₃) receptor (TR) as a heterodimer and mediating T₃ responsiveness of ABCD2 in its promoter context. After a T₃ treatment, an induction of the ABCD2 gene was observed in the liver of normal rats but not that of TR-/- mice. ABCD2 was not induced in the brain of the T₃-treated rats. However, we report for the first time that induction of the ABCD2 redundant gene is feasible in myelin-producing cells (differentiated CG4 oligodendrocytes). The induction was specific for this cell type because it did not occur in astrocytes. Furthermore, we observed T₃ induction of ABCD2 in human and mouse ABCD1-deficient fibroblasts, which was correlated with normalization of the VLCFA -oxidation. Finally, ABCD3 (PMP70), a close homolog of ABCD2, was also induced by T₃ in the liver of control rats, but not that of TR-/- mice, and in CG4 oligodendrocytes.

Address correspondence to: Dr. Maurice Bugaut, LBMC, Faculté des Sciences Gabriel, 6 Bd Gabriel, 21000 Dijon, France. E-mail: mbugaut{at}u-bourgogne.fr

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