A very long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy.

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative and endocrine disorder resulting from mutations in ABCD1 which encodes a peroxisomal membrane protein in the ATP binding cassette superfamily. The biochemical signature of X-ALD is increased levels of saturated very long-chain fatty acids (VLCFA; carbon chains of 22 or more) in tissues and plasma that has been associated with decreased peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity and decreased peroxisomal VLCFA beta-oxidation. It has been hypothesized that ABCD1, which has no demonstrable VLCS activity itself, has an indirect effect on peroxisomal VLCS activity and VLCFA beta-oxidation by transporting fatty acid substrates, VLCS protein or some required co-factor into peroxisomes. Here we report the characterization of a Vlcs knockout mouse that exhibits decreased peroxisomal VLCS activity and VLCFA beta-oxidation but does not accumulate VLCFA. The XALD/Vlcs double knockout mouse has the biochemical abnormalities observed in the individual knockout mice but does not display a more severe X-ALD phenotype. These data lead us to conclude that (1) VLCFA levels are independent of peroxisomal fatty acid beta-oxidation, (2) there is no ABCD1/VLCS interaction and (3) the common severe forms of X-ALD cannot be modeled by decreasing peroxisomal VLCS activity in the XALD mouse.

• Authors: Ann K Heinzer, Paul A Watkins, Jyh-Feng Lu, Stephan Kemp, Ann B Moser, Yuan Yuan Li, Stephanie Mihalik, James M Powers, Kirby D Smith
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 12 Issue 10 Pg. 1145-54 (May 15 2003) ISSN: 0964-6906 [Print] England
• PMID: 12719378 (Publication Type: Journal Article)

Chemical References

• ABCD1 protein, human
• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters
• Fatty Acids
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• Coenzyme A Ligases
• FAA2 protein, S cerevisiae
• long-chain-fatty-acid-CoA ligase

Topics

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Adrenoleukodystrophy (enzymology, genetics)
• Animals
• Brain (enzymology)
• Coenzyme A Ligases (deficiency, genetics)
• Fatty Acids (metabolism)
• Humans
• Kidney (enzymology)
• Liver (enzymology)
• Mice
• Mice, Knockout
• Repressor Proteins
• Saccharomyces cerevisiae Proteins