X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism, ABC half-transporters and the complicated route to treatment

Mol Genet Metab. 2007 Mar;90(3):268-76. doi: 10.1016/j.ymgme.2006.10.001. Epub 2006 Nov 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D
  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters / chemistry
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Adrenoleukodystrophy / drug therapy
  • Adrenoleukodystrophy / genetics
  • Adrenoleukodystrophy / metabolism*
  • Animals
  • Dimerization
  • Fatty Acids / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Mutation
  • Peroxisomes / metabolism
  • Phenylbutyrates / pharmacology

Substances

  • ABCD1 protein, human
  • ABCD2 protein, human
  • ABCD3 protein, human
  • ATP Binding Cassette Transporter, Subfamily D
  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters
  • Fatty Acids
  • Phenylbutyrates
  • 4-phenylbutyric acid