Adrenoleukodystrophy Protein-Deficient Mice Represent Abnormality of Very Long Chain Fatty Acid Metabolism

Kobayashi, Takuya; Shinnoh, Nobue; Kondo, Akira; Yamada, Takeshi

doi:10.1006/bbrc.1997.6340

Cited by 181 publications

(112 citation statements)

References 15 publications

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“…Scattered striated cells, occasionally ballooned, are seen at the light microscopic level, and the identical lamellar-lipid profiles as in the human disease (see Figure 2a) are observed ultrastructurally as early as 3 months of age. 5 Based on the available data (i.e., clinical, functional and pathologic) from the nervous system and adrenal, [8][9][10][11][13][14][15] we believe that the abcd1 KO mouse best recapitulates the myelopathic ALD female heterozygote, not the male ALD/AMN hemizygotes. 1,31 …”

Section: Discussionmentioning

confidence: 98%

“…6,8 Mice lacking abcd1 or abcd2 have failed to reproduce the inflammatory cerebral demyelination characteristic of human ALD. [8][9][10] The major CNS lesion in the aged abcd1 KO (ALD) mouse, as well as in the aged abcd2 KO mouse and abcd1/abcd2 double KO mice, is spinal axonal degeneration that is reminiscent of AMN. 6,11,12 However, the adrenocortical cells of our abcd1 KO mouse exhibit the same lamellar and lipid profiles, detectable with the electron microscope, as those seen in both human ALD and AMN (ALD/AMN).…”

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confidence: 99%

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The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage

Barron-Casella

Deering

et al. 2007

Laboratory Investigation

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X-linked adreno-leukodystrophy is a progressive, systemic peroxisomal disorder that primarily affects the adrenal cortex, as well as myelin and axons of the central nervous system. Marked phenotypic heterogeneity does not correlate with disease-causing mutations in ABCD1, which encodes a peroxisomal membrane protein that is a member of the ABC transmembrane transporter proteins. The precise physiological functions of ABCD1 and ABCD2, a closely related peroxisomal membrane half-transporter, are unknown. The abcd1 knockout mouse does not develop the inflammatory demyelination so typical and devastating in adreno-leukodystrophy, but it does display the same lamellae and lipid profiles in adrenocortical cells under the electron microscope as the human patients. The adrenocortical cells in the mouse also exhibit immunohistochemical evidence of oxidative stress at 12 weeks but no evidence of oxidative damage. To better understand the pathogenesis of this complex disease, we evaluate the adrenal lesion of the abcd1 knockout mouse as a function of normal aging, dietary or therapeutic manipulations, and abcd genotype. The loss of abcd2 causes oxidative stress in the adrenal at 12 weeks, as judged by increased immunoreactivity for the mitochondrial manganese superoxide dismutase, in both the inner cortex and medulla. The loss of abcd2 (n ¼ 20), but not abcd1 (n ¼ 27), results in the spontaneous and premature deposition of ceroid, a known end-product of oxidative damage, predominantly in adrenal medullary cells. These data indicate that the loss of abcd2 results in greater oxidative stress in murine adrenal cells than the loss of abcd1, providing a clue to its cellular function. We also find that the adrenocortical lesion of the abcd1 knockout mouse does not produce functional impairment at ten to nineteen months or overt hypocortisolism at any age, nor does it progress histologically; these and other data align this mouse model closer to human female heterozygotes than to male ALD or AMN hemizygotes.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage

Barron-Casella

Deering

et al. 2007

Laboratory Investigation

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“…Tissues from knockout (KO) mice lacking ABCD1 have a marked increase of VLCFA levels, but normal rates of β-oxidation [45,56]. These mice do not develop an inflammatory cerebral phenotype nor adrenal insufficiency like seen in human X-ALD [57][58][59]. Double KO mice deficient in ABCD1 and ABCD2 exhibit some inflammation, but no cerebral demyelination.…”

Section: Animal Modelsmentioning

confidence: 99%

“…PEX5 mutants have no deficits at birth, but develop a severe phenotype during later life including progressive ataxia, associated by VLCFA accumulation, progressive cerebral demyelination and neuroinflammation. As ABCD1 and PEX5 mutants show comparable increases of VLCFA levels in whole brain lysates (about fourfold elevation) [57][58][59]63], the inflammatory demyelination seen in PEX5 mutants is therefore unlikely to be a result of VLCFA accumulation alone.…”

Section: Animal Modelsmentioning

confidence: 99%

Therapy of X-linked adrenoleukodystrophy

Semmler

Köhler

Jung

et al. 2008

Expert Review of Neurotherapeutics

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X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) onset leading to death within a few years, over adult-onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades, or adrenal insufficiency only. Approximately 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not prove to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Hormone-replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates for future X-ALD therapies. Future Drugs Ltd: Peer Review PaperPlease return your comments for the attention of the Commissioning Editor at l.tipton@expert-reviews.com Many thanks in advance for your kind assistance. Therapy of X-linked Adrenoleukodystrophy Future Drugs Ltd: Peer Review PaperPlease return your comments for the attention of the Commissioning Editor at l.tipton@expert-reviews.com Many thanks in advance for your kind assistance. et al 1963 [6]. In 1981 the X-ALD locus was mapped to chromosome Xq28 [7], and twelve years later, the X-ALD gene (ABCD1) was identified [8,9]. Today X-ALD has been identified in most countries worldwide and in most ethnic groups. The minimum frequency of hemizygotes in the UnitedStates was determined to be 1:42,000 and the one of hemizygotes plus heterozygotes 1:16,800, suggesting X-ALD as the most common inherited leukodystrophy [10]. X-ALD phenotypesX-ALD is characterized by a highly variable clinical spectrum, from early progressive childhood to mild adulthood disease with only slow symptom progre...

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“…Several X-ALD knockout mice have been generated by our group and others (13)(14)(15). All accumulate tissue VLCFA, and fibroblasts derived from these mice have defects in VLCFA ␤-oxidation.…”

mentioning

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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Adrenoleukodystrophy Protein-Deficient Mice Represent Abnormality of Very Long Chain Fatty Acid Metabolism

Cited by 181 publications

References 15 publications

The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage

The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage

Therapy of X-linked adrenoleukodystrophy

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

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