ABC Subfamily D Proteins and Very Long Chain Fatty Acid Metabolism as Novel Targets in Adrenoleukodystrophy

Peroxisomes are involved in a variety of metabolic processes, including beta-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 beta-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 beta-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.