Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy.
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 PPARalpha 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.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM.ULP and Collè de France. Illkirch, CU de Strasbourg, France. apujol@igbmc.u-strasbg.fr
Aurora
A
Pujol
Isidre
I
Ferrer
Carme
C
Camps
Elisabeth
E
Metzger
Colette
C
Hindelang
Noëlle
N
Callizot
Montse
M
Ruiz
Teresa
T
Pàmpols
Marisa
M
Giròs
Jean Louis
JL
Mandel
D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000311:Adrenal Glands / Q000473:pathology / Q000648:ultrastructure; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010641:Phenotype; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure
C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters