Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy

• Published in: Human molecular genetics Vol. 13; no. 23; pp. 2997 - 3006
• Main Authors: Pujol, Aurora, Ferrer, Isidre, Camps, Carme, Metzger, Elisabeth, Hindelang, Colette, Callizot, Noëlle, Ruiz, Montse, Pàmpols, Teresa, Giròs, Marisa, Mandel, Jean Louis
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.12.2004; Oxford Publishing Limited (England); Oxford University Press (OUP)
• Subjects: Adrenal Glands - pathology; Adrenal Glands - ultrastructure; Adrenoleukodystrophy - genetics; Adrenoleukodystrophy - pathology; Animals; ATP Binding Cassette Transporter, Sub-Family D; ATP Binding Cassette Transporter, Sub-Family D, Member 1; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Errors of metabolism; Fundamental and applied biological sciences. Psychology; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Life Sciences; Lipids (lysosomal enzyme disorders, storage diseases); Medical sciences; Metabolic diseases; Mice; Mice, Mutant Strains; Mice, Transgenic; Microscopy, Electron; Molecular and cellular biology; Phenotype; Spinal Cord - pathology; Spinal Cord - ultrastructure; Endocrinopathy; Sex linked character; Nervous system diseases; Metabolic diseases; Lipids; Sphingolipidosis; Enzymopathy; Cerebral disorder; Genetic disease; Adrenoleukodystrophy; Adrenal gland diseases; Central nervous system disease; Genetics; Lipoidosis
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddh323

X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease caused by loss of function of the peroxisomal transporter ABCD1 (ALD), which results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination and peripheral axonopathy and Addison's disease. Knockout of the ALD gene in the mouse (ALD−) results in an adrenomyeloneuropathy-like disease (a late onset form of X-ALD). In the present study, we demonstrate that axonal damage occurs as first pathological event in this model, followed by myelin degeneration. We show that this phenotype can be modulated through expression levels of an ALD-related gene (ALDR/ABCD2), its closest paralogue and a target of PPARα and SREBP transcription factors. Overexpression of ALDR in ALD− mice prevents both VLCFAs accumulation and the neurodegenerative features, whereas double mutants for ALD and ALDR exhibit an earlier onset and more severe disease (including signs of inflammatory reaction) when compared with ALD single mutants. Thus, our results provide direct evidence for functional redundancy/overlap between both transporters in vivo and highlight ALDR as therapeutic target for treatment of X-ALD.