Human Molecular Genetics Advance Access originally published online on October 15, 2004
Human Molecular Genetics 2004 13(23):2997-3006; doi:10.1093/hmg/ddh323
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Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved
Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP and Collège de France, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France, 2Institut de Neuropatologia, Hospital Universitari de Bellvitge, 08907 L'Hospitalet de Llobregat, Barcelona, Spain, 3Institut de Bioquimica Clinica, c/Mejia Lequerica, s/n 08028 Barcelona, Spain and 4Societé Neurofit, SA 67404 Illkirch Cedex, CU de Strasbourg, France
Received August 15, 2004; Accepted October 1, 2004
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 PPAR
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.
* To whom correspondence should be addressed. Email: apujol{at}igbmc.u-strasbg.fr
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