title: Substrate specificity overlap and interaction between adrenoleukodystrophy protein (ALDP/ABCD1) and adrenoleukodystrophy-related protein (ALDRP/ABCD2).
abstract: 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.
authors.affiliation: From the INSERM, UMR866, Centre de Recherche Lipides, Nutrition, Cancer, Dijon F-21000,; the Université de Bourgogne, Laboratoire de Biochimie Métabolique et Nutritionnelle (LBMN), GDRCNRS 2583, 6 Bd Gabriel, Dijon F-21000, and.
authors.forename: Emmanuelle C
authors.initials: EC
authors.lastname: Genin
authors.affiliation: From the INSERM, UMR866, Centre de Recherche Lipides, Nutrition, Cancer, Dijon F-21000,; the Université de Bourgogne, Laboratoire de Biochimie Métabolique et Nutritionnelle (LBMN), GDRCNRS 2583, 6 Bd Gabriel, Dijon F-21000, and.
authors.forename: Flore
authors.initials: F
authors.lastname: Geillon
authors.affiliation: From the INSERM, UMR866, Centre de Recherche Lipides, Nutrition, Cancer, Dijon F-21000,; the Université de Bourgogne, Laboratoire de Biochimie Métabolique et Nutritionnelle (LBMN), GDRCNRS 2583, 6 Bd Gabriel, Dijon F-21000, and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gondcaille
authors.affiliation: Plateforme de Lipidomique-IFR100, Hôpital du Bocage, Dijon F-21000, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Athias
authors.affiliation: Plateforme de Lipidomique-IFR100, Hôpital du Bocage, Dijon F-21000, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gambert
authors.affiliation: From the INSERM, UMR866, Centre de Recherche Lipides, Nutrition, Cancer, Dijon F-21000,; the Université de Bourgogne, Laboratoire de Biochimie Métabolique et Nutritionnelle (LBMN), GDRCNRS 2583, 6 Bd Gabriel, Dijon F-21000, and.
authors.forename: Doriane
authors.initials: D
authors.lastname: Trompier
authors.affiliation: From the INSERM, UMR866, Centre de Recherche Lipides, Nutrition, Cancer, Dijon F-21000,; the Université de Bourgogne, Laboratoire de Biochimie Métabolique et Nutritionnelle (LBMN), GDRCNRS 2583, 6 Bd Gabriel, Dijon F-21000, and. Electronic address: stsavary@u-bourgogne.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Savary
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000201:enzymology* / Q000235:genetics; D051381:Rats
chemical_list: D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; C525916:Abcd2 protein, rat; D005227:Fatty Acids