Cystamine increases <scp>l</scp>‐cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation

Fox, Jonathan H.; Barber, David S.; Singh, Bhupinder; Zucker, Birgit; Swindell, Mary K.; Norflus, Fran; Buzescu, Rodica; Chopra, Raman; Ferrante, Robert J.; Kazantsev, Aleksey G.; Hersch, Steven M.

doi:10.1111/j.1471-4159.2004.02726.x

Cited by 121 publications

(121 citation statements)

References 50 publications

(55 reference statements)

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“…In accordance with these data, GPx1 transcription levels were shown to be increased in three clones of striatal cells expressing mHtt, compared to wild-type cells [14]. Nevertheless, decreased GPx activity was found in erythrocytes of HD patients compared to control individuals [8], whereas in striatal tissue of R6/ 1 HD mice GPx activity was not different [26], and GPx transcription was unaltered in R6/2 HD mice [36], compared with wild-type mice. Concordantly with our study, an increase in GRed activity was found in erythrocytes from HD patients, compared to control individuals [37] and increased GRed transcription was found in the basal ganglia of R6/2 HD mice [36], suggesting a repository mechanism of GSH levels.…”

Section: Discussionsupporting

confidence: 71%

“…Nevertheless, decreased GPx activity was found in erythrocytes of HD patients compared to control individuals [8], whereas in striatal tissue of R6/ 1 HD mice GPx activity was not different [26], and GPx transcription was unaltered in R6/2 HD mice [36], compared with wild-type mice. Concordantly with our study, an increase in GRed activity was found in erythrocytes from HD patients, compared to control individuals [37] and increased GRed transcription was found in the basal ganglia of R6/2 HD mice [36], suggesting a repository mechanism of GSH levels. We also observed increased activity of NADPH-producing enzymes of the pentose-phosphate pathway (G6PD and 6PGD), which is relevant since NADPH is an important cofactor of GRed.…”

Section: Discussionmentioning

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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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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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“…While cystamine may have anti-oxidant and anti-apoptotic properties, it is a potent transglutaminase inhibitor and significantly reduces the formation of Htt aggregates and sequestration of transcription factors critical to cell survival (30). Although the pathological significance of cytosolic and nuclear mtHtt aggregation remains unclear, the evidence continues to point to a proximal toxicity residing in mtHtt, its proteolytic fragments, and their interactions with other proteins.…”

Section: Discussionmentioning

confidence: 99%

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

Ryu

Lee

Hagerty

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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284

252

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Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered chromatin modulation and transcription dysfunction may play a role in the pathogenesis of Huntington's disease (HD). Increased histone methylation, a well established mechanism of gene silencing, results in transcriptional repression. ERG-associated protein with SET domain (ESET), a histone H3 (K9) methyltransferase, mediates histone methylation. We show that ESET expression is markedly increased in HD patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 mice. We further demonstrate that both specificity protein 1 (Sp1) and specificity protein 3 (Sp3) act as transcriptional activators of the ESET promoter in neurons and that mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic, interferes with the DNA binding of these Sp family transcription factors, suppressing basal ESET promoter activity in a dose dependent manner. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype in the R6/2 mice and extended survival over 40%, well beyond any existing reported treatment in HD mice. Our data suggest that modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients. H untington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded stretches of CAG repeats coding for glutamine in the Huntingtin (Htt) gene. Polyglutamine [poly(Q)] expansions of mutant Htt (mtHtt) protein lead to a number of cellular abnormalities that include altered nucleosome dynamics and subsequent transcriptional dysregulation (1-4). Consistent with transcriptional repression playing a role in the pathogenesis of HD, decreased acetylation and increased methylation of histones, well established mechanisms of gene activation and silencing, have been found in HD experimental models (5-8). Histone acetylation is involved in the regulation of gene expression and is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs) (9). The poly(Q) stretches in mtHtt interact physically with CREB binding protein (CBP), a transcriptional coactivator, and block intrinsic CBP histone acetyltransferase activity (2, 5). These specific interactions have led to a model in which mtHtt, by harboring extra glutamines, becomes a hyperactive glutamine-containing corepressor (10). Transcriptional repression may also be attributable to epigenetic modifications, such as histone methylation and histone deacetylation (11). Thus, transcriptional dysfunction has been proposed to play an important role in the neuronal cell death of HD and has be...

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“…Cystamine is an organic disulfide formed from the dimer of cysteine, cystine, through decarboxylation. Recent studies show that administration of cystamine raises cysteine levels in the brain of both R6/2 mice (Fox et al, 2004) and transgenic mice expressing full-length mutant Htt (YAC128 mice) (Pinto et al, 2005). Cystamine also protects 3-NP-induced mitochondrial dysfunction in immortal Hdh111Q striatal cells (Mao et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Rab11-Dependent Trafficking of the Neuronal Glutamate Transporter EAAC1 Causes Oxidative Stress and Cell Death in Huntington's Disease

Li¹,

Valencia²,

Sapp³

et al. 2010

J. Neurosci.

139

122

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Oxidative stress contributes to neurodegeneration in Huntington's disease (HD). However, the origins of oxidative stress in HD remain unclear. Studies in HD transgenic models suggest involvement of mitochondrial dysfunction, which would lead to overproduction of reactive oxygen species (ROS). Impaired mitochondria complexes occur in late stages of HD but not in presymptomatic or early-stage HD patients. Thus, other mechanisms may account for the earliest source of oxidative stress caused by endogenous mutant huntingtin. Here, we report that decreased levels of a major intracellular antioxidant glutathione coincide with accumulation of ROS in primary HD neurons prepared from embryos of HD knock-in mice (HD 140Q/140Q ), which have human huntingtin exon 1 with 140 CAG repeats inserted into the endogenous mouse huntingtin gene. Uptake of extracellular cysteine through the glutamate/cysteine transporter EAAC1 is required for de novo synthesis of glutathione in neurons. We found that, compared with wild-type neurons, HD neurons had lower cell surface levels of EAAC1 and were deficient in taking up cysteine. Constitutive trafficking of EAAC1 from recycling endosomes relies on Rab11 activity, which is defective in the brain of HD 140Q/140Q mice. Enhancement of Rab11 activity by expression of a dominant-active Rab11 mutant in primary HD neurons ameliorated the deficit in cysteine uptake, increased levels of intracellular glutathione, normalized clearance of ROS, and improved neuronal survival. Our data support a novel mechanism for oxidative stress in HD: Rab11 dysfunction slows trafficking of EAAC1 to the cell surface and impairs cysteine uptake, thereby leading to deficient synthesis of glutathione.

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Cystamine increases l‐cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation

Cited by 121 publications

References 50 publications

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

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

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

Aberrant Rab11-Dependent Trafficking of the Neuronal Glutamate Transporter EAAC1 Causes Oxidative Stress and Cell Death in Huntington's Disease

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