Disease relevance of Abcd1

• Inherited defects in ALDP cause the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) [1].
• X-linked adrenoleukodystrophy (X-ALD) is an inherited demyelinating disorder due to mutations in the ALD gene, which encodes a peroxisomal ABC half-transporter (ALDP) [2].
• Motor functions in ALDP-deficient mice developed at schedule, and unexpectedly, adult animals appeared unaffected by neurologic symptoms up to at least 6 months of age [3].
• In its severe form, X-linked adrenoleukodystrophy (ALD) is a lethal neurologic disease of children, characterized by progressive cerebral demyelination and adrenal insufficiency [3].
• Treatment with 0.1% lovastatin significantly reduced body weight and total cholesterol in the plasma of ALDP-deficient mice [4].

High impact information on Abcd1

• Normal bone marrow cells from nonleukemic AKR/J, nonleukemic AKR(Rb6.15) Ald, and tumor passage recipients had similar baseline and 1,3-bis(2-chloroethyl)-1-nitrosourea-induced SCE frequencies following exposure to 4.4 mg 1,3-bis(2-chloroethyl)-1-nitrosourea per kg and 19 hr 5-bromo-2-deoxyuridine [5].
• Mouse very long-chain acyl-CoA synthetase in X-linked adrenoleukodystrophy [6].
• In ALD, very long-chain acyl-coenzyme A synthetase (VLACS), which is necessary for peroxisomal beta-oxidation, does not function [7].
• Adrenoleukodystrophy protein enhances association of very long-chain acyl-coenzyme A synthetase with the peroxisome [7].
• BACKGROUND: X-linked adrenoleukodystrophy (ALD) is characterized biochemically by the accumulation of very long-chain fatty acids (VLCFA) in tissues and body fluids, and is caused by impairment of peroxisomal beta-oxidation [7].

Biological context of Abcd1

• We found evidence for other sequences in the mouse genome related to the 3' end of Aldgh [8].
• This study paves the way for the construction of gene-targeting plasmids that may be used to develop an animal model of ALD [8].
• We dietary treated ALD mice with simvastatin, an analog of lovastatin with similar pharmacokinetics and effects on plasma VLCFA in ALD patients at 20 or 60 mg/kg/day for 6-12 weeks [9].

Anatomical context of Abcd1

• VLACS or ALDP were transiently expressed by lipofection in murine fibroblasts, and VLCFA beta-oxidation was assayed [7].
• Pharmacological approaches aiming at overexpressing the adrenoleukodystrophy-related gene in the central nervous system of adrenoleukodystrophy patients might thus offer new therapeutic leads [10].
• Western blot analysis showed absence of ALDP in the brain, spinal cord, lung, and kidney [11].
• ALDP is highly expressed in astrocytes and microglial cells in vivo and in regenerating oligodendrocytes in vitro [12].
• Protein fractionation and confocal laser imaging of Bgm-green fluorescent protein fusion proteins revealed a microsomal localization that was different from peroxisomes (where Aldp is detected), endoplasmic reticulum and Golgi [13].

Associations of Abcd1 with chemical compounds

• Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, normalizes VLCFA in fibroblasts and plasma from ALD patients [9].
• Simvastatin does not normalize very long chain fatty acids in adrenoleukodystrophy mice [9].

Physical interactions of Abcd1

• The adrenoleukodystrophy gene encodes a peroxisomal membrane protein that is part of a family of related ATP-binding transporters including the adrenoleukodystrophy-related protein [10].

Other interactions of Abcd1

• The expression of ALDP and of two peroxisomal enzymes involved in beta-oxidation of VLCFA, acyl-CoA oxidase, and catalase was studied in human and mouse brain [12].
• Mouse liver PMP70 and ALDP: homomeric interactions prevail in vivo [14].
• It has been suggested that a gene termed bubblegum (Bgm), encoding an acyl-CoA synthetase, could be involved in the pathogenesis of the inherited neurodegenerative disorder X-ALD (X-linked adrenoleukodystrophy) [13].

Analytical, diagnostic and therapeutic context of Abcd1

• OBJECTIVE: To clarify the function of adrenoleukodystrophy protein (ALDP) using our ALDP-deficient mice established by gene targeting [7].
• These data are of importance for the use of ALDP-deficient mice as a model in pharmacological gene therapy studies [1].
• To analyze the cellular function of ALDP and to obtain an animal model of this debilitating disease, we have generated transgenic mice with a targeted inactivation of the ald gene [3].
• The ALDP-containing protein complex was characterized by preparative immunoprecipitation experiments [14].

References