Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington’s disease patients

Chen, Chiung‐Mei; Wu, Yih‐Ru; Cheng, Mei‐Ling; Liu, Junliang; Lee, Yu‐May; Lee, Po-Wei; Soong, Bing‐Wen; Chiu, Daniel T.

doi:10.1016/j.bbrc.2007.05.093

Cited by 203 publications

(170 citation statements)

References 31 publications

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“…An increase in SOD activity was previously observed in R6/1 HD mice at 19 weeks of age, although older mice exhibited decreased SOD activity [70]. Reduced activity of SOD1 was also observed in cortex and cerebellum of post-mortem human brain tissues [7] and in erythrocytes [5] of HD patients. In a previous study we demonstrated increased ROS levels and decreased GCL activity, despite increased glutathione levels in HD striatal cells, which occurred as a result of a lower capacity of multidrug resistance-associated protein 1 (Mrp1) to export GSH to the extracellular space [17].…”

Section: Discussionmentioning

confidence: 52%

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Oliveira

et al. 2014

Free Radical Biology and Medicine

117

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Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j. freeradbiomed.2014.06.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 52%

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Oliveira

et al. 2014

Free Radical Biology and Medicine

117

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“…In HD patients' blood plasma, elevated levels of 8-OH-dG were observed [8,11]. Also, increased levels of 8-OH-dG [8] and MDA [6] were previously observed, respectively, in leukocytes and serum of HD patients. Concordantly, in R6/2 HD mice (expressing exon 1 of the human HD gene), 8-OH-dG levels were shown to be increased in striatum, urine, and plasma [12].…”

Section: Introductionmentioning

confidence: 53%

“…Furthermore, increases in mRNA levels of GPx1, catalase, and SOD1 (Cu/Zn-SOD) were observed in striatal cells expressing full-length mHtt (FL-mHtt) [14]; however, these studies did not analyze the enzymatic activities of the antioxidant systems. Conversely, in erythrocytes from HD patients, GPx and SOD1 activities were found to be decreased, compared to unaffected subjects [8], suggesting an impairment of the antioxidant defenses in HD peripheral samples.…”

Section: Introductionmentioning

confidence: 76%

“…Oxidative stress is one of several dysfunctional mechanisms described in HD [4][5][6][7][8], which may result from impaired mitochondrial function, namely due to interaction of the organelle with mHtt [9] and/or imbalanced levels of antioxidants.…”

Section: Introductionmentioning

confidence: 99%

“…In HD postmortem tissues, levels of 8-hydroxydeoxyguanosine (8-OH-dG), a DNA oxidative damage marker, and malondialdehyde (MDA), a lipid peroxidation marker, were increased in caudate nucleus and parietal cortex [4,10]. In HD patients' blood plasma, elevated levels of 8-OH-dG were observed [8,11]. Also, increased levels of 8-OH-dG [8] and MDA [6] were previously observed, respectively, in leukocytes and serum of HD patients.…”

Section: Introductionmentioning

confidence: 99%

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Glutathione redox cycle dysregulation in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Cunha‐Oliveira

et al. 2012

Free Radical Biology and Medicine

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a b s t r a c tHuntington's disease (HD) is a CAG repeat disorder affecting the HD gene, which encodes for huntingtin (Htt) and is characterized by prominent cell death in the striatum. Oxidative stress was previously implicated in HD neurodegeneration, but the role of the major endogenous antioxidant system, the glutathione redox cycle, has been less studied following expression of full-length mutant Htt (FL-mHtt). Thus, in this work we analyzed the glutathione system in striatal cells derived from HD knock-in mice expressing mutant Htt versus wild-type cells. Mutant cells showed increased intracellular reactive oxygen species (ROS) and caspase-3 activity, which were significantly prevented following treatment with glutathione ethyl ester. Interestingly, mutant cells exhibited an increase in intracellular levels of both reduced and oxidized forms of glutathione, and enhanced activities of glutathione peroxidase (GPx) and glutathione reductase (GRed). Furthermore, glutathione-S-transferase (GST) and g-glutamyl transpeptidase (g-GT) activities were also increased in mutant cells. Nevertheless, glutamate-cysteine ligase (GCL) and glutathione synthetase (GS) activities and levels of GCL catalytic subunit were decreased in cells expressing FL-mHtt, highly suggesting decreased de novo synthesis of glutathione. Enhanced intracellular total glutathione, despite decreased synthesis, could be explained by decreased extracellular glutathione in mutant cells. This occurred concomitantly with decreased mRNA expression levels and activity of the multidrug resistance protein 1 (Mrp1), a transport protein that mediates cellular export of glutathione disulfide and glutathione conjugates. Additionally, inhibition of Mrp1 enhanced intracellular GSH in wild-type cells only. These data suggest that FL-mHtt affects the export of glutathione by decreasing the expression of Mrp1. Data further suggest that boosting of GSH-related antioxidant defense mechanisms induced by FL-mHtt is insufficient to counterbalance increased ROS formation and emergent apoptotic features in HD striatal cells.

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Neuroinflammation in Alzheimer's, Parkinson's and Huntington's Diseases

Sastre

Katsouri

Birch

et al. 2014

Neuroinflammation and CNS Disorders

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Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington’s disease patients

Cited by 203 publications

References 31 publications

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Glutathione redox cycle dysregulation in Huntington’s disease knock-in striatal cells

Neuroinflammation in Alzheimer's, Parkinson's and Huntington's Diseases

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