Peroxisomes are involved in a variety of metabolic processes, including β-oxidation of
fatty acids, especially very long chain
fatty acids. Three peroxisomal ABC
proteins belonging to subfamily D have been identified in mammalian peroxisomes that have an important role in
fatty acid metabolism. ABCD1/ALDP and ABCD2/ALDRP are suggested to be involved in the transport of very
long chain acyl-CoA, and ABCD3/PMP70 is involved in the transport of
long chain acyl-CoA. ABCD1 is known to be responsible for
X-linked adrenoleukodystrophy (
X-ALD); an inborn error of peroxisomal β-oxidation of very long chain
fatty acids.
X-ALD is characterized biochemically by the accumulation of very long chain
fatty acids in all tissues, including the brain white matter. Progressive
demyelination of the central nervous system and adrenal dysfunction have been observed. The pharmacological up-regulation of peroxisomal β-oxidation of very long chain
fatty acids and the suppression of
fatty acid elongation are important aspects of an optimal therapeutic approach. Attractive targets for the treatment of
X-ALD patients include the ABCD2 as well as elongase that is involved in the elongation of very long chain
fatty acids. In addition, stabilization of mutant ABCD1 that has retained some of its function might be another approach, since most of the mutant ABCD1s with a missense mutation are degraded rapidly by proteasomes before or after targeting to peroxisomes. Protection of the central nervous system against oxidative damage is also important in order to delay the progress of disease. We summarize recent
pharmaceutical studies and consider the potential for future
X-ALD therapies.