Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy.
Inherited defects in the peroxisomal ATP-binding cassette (ABC) transporter adrenoleukodystrophy protein (ALDP) lead to the lethal peroxisomal disorder X-linked adrenoleukodystrophy (X-ALD), for which no efficient treatment has been established so far. Three other peroxisomal ABC transporters currently are known: adrenoleukodystrophy-related protein (ALDRP), 70 kDa peroxisomal membrane protein (PMP70) and PMP70- related protein. By using transient and stable overexpression of human cDNAs encoding ALDP and its closest relative ALDRP, we could restore the impaired peroxisomal beta-oxidation in fibroblasts of X-ALD patients. The pathognomonic accumulation of very long chain fatty acids could also be prevented by overexpression of ALDRP in immortalized X-ALD cells. Immunofluorescence analysis demonstrated that the functional replacement of ALDP by ALDRP was not due to stabilization of the mutated ALDP itself. Moreover, we were able to restore the peroxisomal beta-oxidation defect in the liver of ALDP-deficient mice by stimulation of ALDRP and PMP70 gene expression through a dietary treatment with the peroxisome proliferator fenofibrate. These results suggest that a correction of the biochemical defect in X-ALD could be possible by drug-induced overexpression or ectopic expression of ALDRP.
Netik
A
A
Institute of Neurology, University of Vienna, Schwarzspanierstrasse 17, A-1090 Vienna, Austria.
Forss-Petter
S
S
Holzinger
A
A
Molzer
B
B
Unterrainer
G
G
Berger
J
J
D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008830:Microbodies / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; C063305:ABCD3 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C489271:Abcd3 protein, mouse; D005227:Fatty Acids; D008565:Membrane Proteins; D011506:Proteins; D011994:Recombinant Proteins; D011345:Fenofibrate