Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington’s disease gene carriers and healthy subjects

Klepac, Nataša; Relja, Maja; R, Klepac; Hečimović, Silva; Babić, Tomislav; Trkulja, Vladimir

doi:10.1007/s00415-007-0611-y

Cited by 159 publications

(99 citation statements)

References 35 publications

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“…In addition, decreased GSH levels and higher lipid peroxidation were observed in the plasma of HD symptomatic and asymptomatic individuals, compared to ageand sex-matched controls, suggesting that oxidative stress may occur before the onset of HD symptoms [34]. Conversely, the levels of mitochondrial GSH were increased in the striatum and cortex of R6/2 HD mice compared to wild-type animals, suggesting a compensatory mechanism to counteract the increase in mitochondrial ROS generation [16], which may also help to explain our data.…”

Section: Discussionmentioning

confidence: 97%

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: Discussionmentioning

confidence: 97%

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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“…31 Interestingly, these inducers have been shown to participate in HD. 32,33 Moreover, striatal membrane fractions from the N171-82Q HD mouse model show increased levels of PI3K, 34 which could result in higher levels of Akt activation. In the HD cell model STHdh Q111/Q111 enhanced NMDAR signaling upregulates Akt activity, 12 and here we show that this also occurs in R6/1 mice striatum as increased pAkt (Ser473) levels were observed after QUIN injection.…”

Section: Discussionmentioning

confidence: 99%

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

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Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh Q111/Q111 mouse striatum and STHdh Q111/Q111 cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF þ /À, R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing.

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“…In addition, S-glutathionylation regulates many proteins involved in endoplasmic reticulum (ER) stress and the unfolded protein response that accompanies oxidative stress (Townsend, 2007). A number of neurodegenerative diseases and psychiatric disorders have been linked to abnormal GSH levels, ER stress, and accompanying S-glutathionylation of proteins, such as Parkinson's disease (Chinta et al, 2006;Sian et al, 1994), Alzheimer's disease (Di Domenico et al, 2009;Zhu et al, 2006), Huntington's disease (Klepac et al, 2007), and schizophrenia (Radonjic et al, 2010;Raffa et al, 2009;Steullet et al, 2006). GSH cannot cross cell membranes and therefore needs to be synthesized de novo.…”

Section: Introductionmentioning

confidence: 99%

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

Uys

Knackstedt

Hurt

et al. 2011

Neuropsychopharmacol

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Impaired glutamate homeostasis in the nucleus accumbens has been linked to cocaine relapse in animal models, and results in part from cocaine-induced downregulation of the cystine-glutamate exchanger. In addition to regulating extracellular glutamate, the uptake of cystine by the exchanger is a rate-limiting step in the synthesis of glutathione (GSH). GSH is critical for balancing cellular redox in response to oxidative stress. Cocaine administration induces oxidative stress, and we first determined if downregulated cystineglutamate exchange alters redox homeostasis in rats withdrawn from daily cocaine injections and then challenged with acute cocaine. Among the daily cocaine-induced changes in redox homeostasis were an increase in protein S-glutathionylation and a decrease in expression of GSH-S-transferase pi (GSTpi). To mimic reduced GSTpi, a genetic mouse model of GSTpi deletion or pharmacological inhibition of GSTpi by administering ketoprofen during daily cocaine administration was used. The capacity of cocaine to induce conditioned place preference or locomotor sensitization was augmented, indicating that reducing GSTpi may contribute to cocaineinduced behavioral neuroplasticity. Conversely, an acute cocaine challenge after withdrawal from daily cocaine elicited a marked increase in accumbens GSTpi, and the expression of behavioral sensitization to a cocaine challenge injection was inhibited by ketoprofen pretreatment; supporting a protective effect by the acute cocaine-induced rise in GSTpi. Together, these data indicate that cocaineinduced oxidative stress induces changes in GSTpi that contribute to cocaine-induced behavioral plasticity.

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Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington’s disease gene carriers and healthy subjects

Abstract: Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington's disease gene carriers and healthy subjects : A crosssectional study. Journal of Neurology, 254 (12). pp. 1676-1683.

Cited by 159 publications

References 35 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

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

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