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 disorde r X-linked adrenoleukodystrophy (X-ALD), for which no efficient treatment h as been established so far. Three other peroxisomal ABC transporters curren tly are known: adrenoleukodystrophy-related protein (ALDRP), 70 kDa peroxis omal membrane protein (PMP70) and PMP70-related protein. By using transient and stable overexpression of human cDNAs encoding ALDP and its closest rel ative ALDRP, we could restore the impaired peroxisomal beta-oxidation in fi broblasts of X-ALD patients. The pathognomonic accumulation of very long ch ain fatty acids could also be prevented by overexpression of ALDRP in immor talized X-ALD cells. Immunofluorescence analysis demonstrated that the func tional replacement of ALDP by ALDRP was not due to stabilization of the mut ated ALDP itself, Moreover, we were able to restore the peroxisomal beta-ox idation defect in the liver of ALDP-deficient mice by stimulation of ALDRP and PMP70 gene expression through a dietary treatment with the peroxisome p roliferator fenofibrate, These results suggest that a correction of the bio chemical defect in X-ALD could be possible by drug-induced overexpression o r ectopic expression of ALDRP.