Adreno-leukodystrophy: Oxidative Stress of Mice and Men

Powers, James M.; Pei, Zhengtong; Heinzer, Ann K.; Deering, Rebecca; Moser, Ann B.; Moser, Hugo W.; Watkins, Paul A.; Smith, Kirby D.

doi:10.1097/01.jnen.0000190064.28559.a4

Cited by 116 publications

(106 citation statements)

References 36 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: 99%

“…The SOD2 immunoreactivities in the 3-month-old abcd1 KO was stronger and more widespread, but restricted to the cortex (data not shown)-as published previously. 15 …”

Section: In Situ Hybridization and Sod2mentioning

confidence: 99%

“…This stands in striking contrast to human ALD where oxidative stress and mild oxidative damage were noted in the adrenal cortex, while profound oxidative damage was seen in the inflammatory cerebral demyelination. 15 The reason for the apparent self-limiting nature of the abcd1 KO mouse adrenal lesion remained unclear; we theorized that its adrenocortical cells were able to adapt to the oxidative stress, at least temporarily (12 weeks), through the overexpression of the anti-oxidant mitochondrial manganese superoxide dismutase (formerly MnSOD, currently SOD2).…”

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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: 99%

“…The SOD2 immunoreactivities in the 3-month-old abcd1 KO was stronger and more widespread, but restricted to the cortex (data not shown)-as published previously. 15 …”

Section: In Situ Hybridization and Sod2mentioning

confidence: 99%

mentioning

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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“…18,19 We previously reported oxidative damage in spinal cords from presymptomatic Abcd1 -mice, [20][21][22] together with metabolic failure, 23 disrupted mitochondrial biogenesis 24 and impaired mitochondrial oxidative phosphorylation and function. [25][26][27] Evidences for oxidative damage in X-ALD patients are also found in brain 28 and blood samples. [29][30][31] In this study.…”

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confidence: 95%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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“…The Wechsler Performance IQ (PIQ) of o80 predicts poor functional outcome after HSCT. 9,10 Based on Powers' work on oxidative stress and damage in ALD, 11 we have explored the use of an agent with antioxidant and radical scavenger capabilities, N-acetyl-L-cysteine (NAC), in an attempt to arrest progression of demyelination in advanced ALD. NAC stimulates glutathione synthesis and scavenges free radicals, which has been hypothesized to provide neuroprotective capacity.…”

Section: Introductionmentioning

confidence: 99%