Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy

Vargas, Carmen Regla; Wajner, Moaçir; Sirtori, Lisana Reginini; Goulart, Laureci da Silva; Chiochetta, Marina; Coelho, Daniela M.; Latini, Alexandra; Llesuy, Susana; Belló‐Klein, Adriane; Giugliani, Roberto; Deon, Marion; Mello, Carlos Fernando

doi:10.1016/j.bbadis.2003.10.004

Cited by 105 publications

(84 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NAC stimulates glutathione synthesis and scavenges free radicals, which has been hypothesized to provide neuroprotective capacity. [12][13][14] Here, we show that administration of NAC before and after HSCT in three patients with advanced ALD resulted in survival of a disease process that would be expected to be lethal.…”

Section: Introductionmentioning

confidence: 71%

N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy

Tolar

Orchard

Bjoraker

et al. 2007

Bone Marrow Transplant

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 71%

N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy

Tolar

Orchard

Bjoraker

et al. 2007

Bone Marrow Transplant

View full text Add to dashboard Cite

“…[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. we demonstrate that the promotion of mitochondrial function through SIRT1 activation emerges as a valuable therapeutic option to prevent axonal demise in X-ALD.…”

mentioning

confidence: 87%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

View full text Add to dashboard Cite

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 ...

show abstract

“…Additionally, oxidative stress and damage likely contribute to cALD pathology. [19][20][21] Rockenbach et al analyzed plasma samples in four cALD boys before and after successful HCT, and demonstrated favorable changes in lipid and protein oxidative damage markers, thus suggesting HCT's ability to decrease oxidative stress pathways in cALD. 22 To date, the field has lacked animal models that recapitulate the dramatic inflammatory demyelination seen in boyhood cALD, thus impeding full elucidation of both the pathophysiology and transplant's mechanistic effect.…”

Section: Allogeneic Hematopoietic Cell Transplantation For Childhoodmentioning

confidence: 99%

Stem cell-transplantation therapy for adrenoleukodystrophy: current perspectives

Miller¹

2017

View full text Add to dashboard Cite

Adrenoleukodystrophy (ALD) is a rare, X-linked peroxisomal disorder of impaired very long-chain fatty-acid metabolism. It results from various mutations in the ABCD1 gene (Xq28). All males with the biochemical defect of ALD are at risk of developing cerebral whitematter disease (cALD) during their lifetime. Thirty-five percent of ALD patients develop cALD in boyhood, a life-threatening phenotype characterized by rapidly expanding, neuroinflammatory demyelination and irreversible clinical neurologic decline. The ABCD1 genotype does not predict susceptibility to or protection from the childhood cALD phenotype; therefore, clinicians must remain ever vigilant for its development when monitoring ALD patients. Currently, allogeneic hematopoietic cell transplantation (HCT) is the standard of care for boyhood cALD. While HCT provides dramatic functional survival benefit in boys with early, presymptomatic cALD, outcomes are less favorable and less predictable for those with more advanced disease. Furthermore, little is known about how successful HCT in childhood might impact the onset of central nervous system disease in adulthood. Finally, investigations of experimental gene-therapy strategies are ongoing. This review explores current perspectives of stem cell transplantation in cALD.

show abstract

Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy

Cited by 105 publications

References 29 publications

N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy

N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Stem cell-transplantation therapy for adrenoleukodystrophy: current perspectives

Contact Info

Product

Resources

About