The protein coded by the X‐adrenoleukodystrophy gene is a peroxisomal integral membrane protein

Abstract

The gene for adrenoleukodystrophy (X-ALD), a peroxisomal disease characterized by excessive accumulation of very long-chain (VLC) fatty acids (> C22: 07, has recently been identified by positional cloning, and it is predicted to encode a protein (ALD-P) of 745 amino acids [(1993) Nature 361, 726]. Using Western blot analysis of subcellular organelles purified by isopycnic density gradient centrifugation from X-ALD and control fibroblasts, we show that the monoclonal antibodies directed against ALD-P cross-react with a 75 kDa protein in intact peroxisomes and that ALD-P is an integral component of the peroxisomal membrane. Moreover, no signal for ALD-P was detected in peroxisomes from X-ALD patients with deletion of the ALD gene.

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

“…The elevation of VLCFAs is the consequence of reduced VLCFA peroxisomal ␤ -oxidation ( 7 ) and/or increased activity of FA elongases ( 8, 9 ). The ALD gene (ABCD1), identifi ed by positional cloning ( 10 ), encodes a protein that is related to the peroxisomal ATP binding cassette (ABCD) transmembrane transporter proteins ( 11,12 ). The function of the adrenoleukodystrophy protein (ALDP) and its role in VLCFA metabolism and in the pathogenesis of X-ALD is not well understood at present.…”

Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia

“…The products of the PMP70 and ALD1 genes, whose mutations are responsible for Zellweger syndrome and adrenoleukodystrophy respectively, are found in the membrane of another type of organelle, the peroxisome (Kamijo et al 1990;Contreras et al 1994). We speculate that dysfunction of the hABC7 protein is involved in X-linked sideroblastic anemia with spinocerebellar ataxia.…”

“…Interestingly, the PMP70 and ALD proteins are located in the membranes of peroxisomes (Kamijo et al 1990;Contreras et al 1994) which, like mitochondria, are organelles.…”

Effects of Lorenzo’s Oil on Peroxisomes in Healthy Mice

“…Catalase induction may be linked to a simultaneous increase in peroxisomal ␤-oxidation: the diet with 20% partially hydrogenated fish oil ϩ 5% soybean oil also induced the cyanide-insensitive palmitoyl-CoA dependent NAD ϩ -reduction (14). A diet with 18.6% olive oil (contained 78.7% oleic acid) did not change antimycin-and rotenoneinsensitive oxidation rates of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C] palmitate in the heart of rats (15). We therefore assume that the induction of myocardial catalase activity in mice treated with Lorenzo's Oil is due to the presence of erucic acid in the diet.…”

“…Peroxisomal ␤-oxidation of very-long-chain fatty acids is deficient. X-linked adrenoleukodystrophy is caused by a defect of a gene coding for an ATP-binding transporter (1). This is believed to affect the import and function of very-long-chain acyl-CoA synthetase in peroxisomes and not the function of peroxisomal acyl-CoA oxidases or of other peroxisomal enzymes.…”