X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism, ABC half-transporters and the complicated route to treatment.
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene that encodes a peroxisomal membrane located ABC half-transporter named ALDP. Mutations in ALDP result in elevated levels of very long-chain fatty acids (VLCFA) and reduced VLCFA beta-oxidation in peroxisomes. The peroxisomal membrane harbors three additional closely related ABC half-transporters, ALDRP, PMP70 and PMP69 (PMP70R). ABC half-transporters must dimerize to form a functional full-transporter. Whether ALDP forms a homodimer or a heterodimer has not yet been resolved, but most indirect evidence favors homodimerization. The peroxisomal ABC half-transporters are functionally related. Over-expression of ALDRP can correct the biochemical defect both in X-ALD patients cells and the Abcd1 knockout mouse, providing an exciting new possibility for treatment of X-ALD patients. This paper provides an overview of current knowledge and the problems that have been encountered.
Kemp
Stephan
S
Academic Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. s.kemp@amc.uva.nl <s.kemp@amc.uva.nl>
Wanders
Ronald J A
RJ
D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019281:Dimerization; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020675:Peroxisomes / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology
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; D005227:Fatty Acids; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid