Impaired Ability of Peroxisomes to Activate Very-Long-Chain Fatty Acids in X-Linked Adrenoleukodystrophy

Wanders, Ronald J. A.; Roermund, C. W. T. van; Schutgens, R. B. H.; Bosch, H. Van Den; Tager, J. M.

doi:10.1016/s0140-6736(88)90729-5

Cited by 19 publications

(2 citation statements)

References 4 publications

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“…All animals were housed under the same controlled conditions, between 22 and 27°C, on a 12-h light/dark cycle, with free access to food and water. Procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance with national and international laws and policies (EEC Council Directive 86/609, OJ L 358, 1 DEC. 12,1987; NIH Guide for the Care and Use of Laboratory Animals, U. S. National Research Council, 1996).…”

Section: Animalsmentioning

confidence: 99%

Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

Heinzer¹,

Kemp²,

Lu³

et al. 2002

Journal of Biological Chemistry

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X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by accumulation of very long-chain fatty acids (VLCFA). This accumulation has been attributed to decreased VLCFA ␤-oxidation and peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity. The X-ALD gene, ABCD1, encodes a peroxisomal membrane ATP binding cassette transporter, ALDP, that is hypothesized to affect VLCS activity in peroxisomes by direct interaction with the VLCS enzyme. Recently, a VLCS gene that encodes a protein with significant sequence identity to known rat and human peroxisomal VLCS protein has been identified in mice. We find that the mouse VLCS gene (Vlcs) encodes an enzyme (Vlcs) with VLCS activity that localizes to peroxisomes and is expressed in X-ALD target tissues. We show that the expression of Vlcs in the peroxisomes of X-ALD mouse fibroblasts improves VLCFA ␤-oxidation in these cells, implying a role for this enzyme in the biochemical abnormality of X-ALD. X-ALD mice, which accumulate VLCFA in tissues, show no change in the expression of Vlcs, the subcellular localization of Vlcs, or general peroxisomal VLCS activity. These observations imply that ALDP is not necessary for the proper expression or localization of Vlcs protein, and the control of VLCFA levels does not depend on the direct interaction of Vlcs and ALDP.

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Section: Animalsmentioning

confidence: 99%

Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

Heinzer¹,

Kemp²,

Lu³

et al. 2002

Journal of Biological Chemistry

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“…Third, although the two recipients of hematopoietic stem cell therapy showed improvement in their neurological symptoms, plasma VLCFA concentrations remained high ( Cartier et al, 2009 ). In addition to the documented role for the ABC transporter in VLCFA metabolism and ALD, a role for the acyl-CoA synthases (ACSs) that function immediately upstream of ABC transporters in fatty acid (FA) metabolism has long been contemplated, as decreased ACS activity is another biochemical hallmark of ALD ( Hashmi et al, 1986 ; Lazo et al, 1988 ; Wanders et al, 1988 ). Consistent with this idea is the recent identification of a patient with ALD-like cerebral degeneration with a rare mutation in the SLC27a6 -encoded ACS ( Sivachenko et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Etiology and treatment of adrenoleukodystrophy: new insights from Drosophila

Gordon

Valdez

Letsou

2018

Disease Models &Amp; Mechanisms

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Adrenoleukodystrophy (ALD) is a fatal progressive neurodegenerative disorder affecting brain white matter. The most common form of ALD is X-linked (X-ALD) and results from mutation of the ABCD1-encoded very-long-chain fatty acid (VLCFA) transporter. X-ALD is clinically heterogeneous, with the cerebral form being the most severe. Diagnosed in boys usually between the ages of 4 and 8 years, cerebral X-ALD symptoms progress rapidly (in as little as 2 years) through declines in cognition, learning and behavior, to paralysis and ultimately to a vegetative state and death. Currently, there are no good treatments for X-ALD. Here, we exploit the Drosophila bubblegum (bgm) double bubble (dbb) model of neurometabolic disease to expand diagnostic power and therapeutic potential for ALD. We show that loss of the Drosophila long-/very-long-chain acyl-CoA synthetase genes bgm and/or dbb is indistinguishable from loss of the Drosophila ABC transporter gene ABCD. Shared loss-of-function phenotypes for synthetase and transporter mutants point to a lipid metabolic pathway association with ALD-like neurodegenerative disease in Drosophila; a pathway association that has yet to be established in humans. We also show that manipulation of environment increases the severity of neurodegeneration in bgm and dbb mutant flies, adding even further to a suite of new candidate ALD disease-causing genes and pathways in humans. Finally, we show that it is a lack of lipid metabolic pathway product and not (as commonly thought) an accumulation of pathway precursor that is causative of neurometabolic disease: addition of medium-chain fatty acids to the diet of bgm or dbb mutant flies prevents the onset of neurodegeneration. Taken together, our data provide new foundations both for diagnosing ALD and for designing effective, mechanism-based treatment protocols..

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