Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease

Humberto Rodriguez-Rocha, Aracely Garcia Garcia, Laura Zavala-Flores, Sumin Li, Nandakumar Madayiputhiya, Rodrigo Franco-Cruz

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Aims: Chronic exposure to environmental toxicants, such as paraquat, has been suggested as a risk factor for Parkinson's disease (PD). Although dopaminergic cell death in PD is associated with oxidative damage, the molecular mechanisms involved remain elusive. Glutaredoxins (GRXs) utilize the reducing power of glutathione to modulate redox-dependent signaling pathways by protein glutathionylation. We aimed to determine the role of GRX1 and protein glutathionylation in dopaminergic cell death. Results: In dopaminergic cells, toxicity induced by paraquat or 6-hydroxydopamine (6-OHDA) was inhibited by GRX1 overexpression, while its knock-down sensitized cells to paraquat-induced cell death. Dopaminergic cell death was paralleled by protein deglutathionylation, and this was reversed by GRX1. Mass spectrometry analysis of immunoprecipitated glutathionylated proteins identified the actin binding flightless-1 homolog protein (FLI-I) and the RalBP1-associated Eps domain-containing protein 2 (REPS2/POB1) as targets of glutathionylation in dopaminergic cells. Paraquat induced the degradation of FLI-I and REPS2 proteins, which corresponded with the activation of caspase 3 and cell death progression. GRX1 overexpression reduced both the degradation and deglutathionylation of FLI-I and REPS2, while stable overexpression of REPS2 reduced paraquat toxicity. A decrease in glutathionylated proteins and REPS2 levels was also observed in the substantia nigra of mice treated with paraquat. Innovation: We have identified novel protein targets of glutathionylation in dopaminergic cells and demonstrated the protective role of GRX1-mediated protein glutathionylation against paraquat-induced toxicity. Conclusions: These results demonstrate a protective role for GRX1 and increased protein glutathionylation in dopaminergic cell death induced by paraquat, and identify a novel protective role for REPS2.

Original languageEnglish (US)
Pages (from-to)1676-1693
Number of pages18
JournalAntioxidants and Redox Signaling
Volume17
Issue number12
DOIs
StatePublished - Dec 15 2012

Fingerprint

Glutaredoxins
Parkinsonian Disorders
Paraquat
Cell death
Cell Death
Proteins
Oxidopamine
Toxicity
Parkinson Disease
Microfilament Proteins
Environmental Exposure
Substantia Nigra
Degradation
Caspase 3
Oxidation-Reduction
Glutathione
Mass Spectrometry
Mass spectrometry
Actins

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease. / Rodriguez-Rocha, Humberto; Garcia Garcia, Aracely; Zavala-Flores, Laura; Li, Sumin; Madayiputhiya, Nandakumar; Franco-Cruz, Rodrigo.

In: Antioxidants and Redox Signaling, Vol. 17, No. 12, 15.12.2012, p. 1676-1693.

Research output: Contribution to journalArticle

Rodriguez-Rocha, Humberto ; Garcia Garcia, Aracely ; Zavala-Flores, Laura ; Li, Sumin ; Madayiputhiya, Nandakumar ; Franco-Cruz, Rodrigo. / Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease. In: Antioxidants and Redox Signaling. 2012 ; Vol. 17, No. 12. pp. 1676-1693.
@article{05ff654d0a5b45f48d4c040fb7d54c76,
title = "Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease",
abstract = "Aims: Chronic exposure to environmental toxicants, such as paraquat, has been suggested as a risk factor for Parkinson's disease (PD). Although dopaminergic cell death in PD is associated with oxidative damage, the molecular mechanisms involved remain elusive. Glutaredoxins (GRXs) utilize the reducing power of glutathione to modulate redox-dependent signaling pathways by protein glutathionylation. We aimed to determine the role of GRX1 and protein glutathionylation in dopaminergic cell death. Results: In dopaminergic cells, toxicity induced by paraquat or 6-hydroxydopamine (6-OHDA) was inhibited by GRX1 overexpression, while its knock-down sensitized cells to paraquat-induced cell death. Dopaminergic cell death was paralleled by protein deglutathionylation, and this was reversed by GRX1. Mass spectrometry analysis of immunoprecipitated glutathionylated proteins identified the actin binding flightless-1 homolog protein (FLI-I) and the RalBP1-associated Eps domain-containing protein 2 (REPS2/POB1) as targets of glutathionylation in dopaminergic cells. Paraquat induced the degradation of FLI-I and REPS2 proteins, which corresponded with the activation of caspase 3 and cell death progression. GRX1 overexpression reduced both the degradation and deglutathionylation of FLI-I and REPS2, while stable overexpression of REPS2 reduced paraquat toxicity. A decrease in glutathionylated proteins and REPS2 levels was also observed in the substantia nigra of mice treated with paraquat. Innovation: We have identified novel protein targets of glutathionylation in dopaminergic cells and demonstrated the protective role of GRX1-mediated protein glutathionylation against paraquat-induced toxicity. Conclusions: These results demonstrate a protective role for GRX1 and increased protein glutathionylation in dopaminergic cell death induced by paraquat, and identify a novel protective role for REPS2.",
author = "Humberto Rodriguez-Rocha and {Garcia Garcia}, Aracely and Laura Zavala-Flores and Sumin Li and Nandakumar Madayiputhiya and Rodrigo Franco-Cruz",
year = "2012",
month = "12",
day = "15",
doi = "10.1089/ars.2011.4474",
language = "English (US)",
volume = "17",
pages = "1676--1693",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "12",

}

TY - JOUR

T1 - Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease

AU - Rodriguez-Rocha, Humberto

AU - Garcia Garcia, Aracely

AU - Zavala-Flores, Laura

AU - Li, Sumin

AU - Madayiputhiya, Nandakumar

AU - Franco-Cruz, Rodrigo

PY - 2012/12/15

Y1 - 2012/12/15

N2 - Aims: Chronic exposure to environmental toxicants, such as paraquat, has been suggested as a risk factor for Parkinson's disease (PD). Although dopaminergic cell death in PD is associated with oxidative damage, the molecular mechanisms involved remain elusive. Glutaredoxins (GRXs) utilize the reducing power of glutathione to modulate redox-dependent signaling pathways by protein glutathionylation. We aimed to determine the role of GRX1 and protein glutathionylation in dopaminergic cell death. Results: In dopaminergic cells, toxicity induced by paraquat or 6-hydroxydopamine (6-OHDA) was inhibited by GRX1 overexpression, while its knock-down sensitized cells to paraquat-induced cell death. Dopaminergic cell death was paralleled by protein deglutathionylation, and this was reversed by GRX1. Mass spectrometry analysis of immunoprecipitated glutathionylated proteins identified the actin binding flightless-1 homolog protein (FLI-I) and the RalBP1-associated Eps domain-containing protein 2 (REPS2/POB1) as targets of glutathionylation in dopaminergic cells. Paraquat induced the degradation of FLI-I and REPS2 proteins, which corresponded with the activation of caspase 3 and cell death progression. GRX1 overexpression reduced both the degradation and deglutathionylation of FLI-I and REPS2, while stable overexpression of REPS2 reduced paraquat toxicity. A decrease in glutathionylated proteins and REPS2 levels was also observed in the substantia nigra of mice treated with paraquat. Innovation: We have identified novel protein targets of glutathionylation in dopaminergic cells and demonstrated the protective role of GRX1-mediated protein glutathionylation against paraquat-induced toxicity. Conclusions: These results demonstrate a protective role for GRX1 and increased protein glutathionylation in dopaminergic cell death induced by paraquat, and identify a novel protective role for REPS2.

AB - Aims: Chronic exposure to environmental toxicants, such as paraquat, has been suggested as a risk factor for Parkinson's disease (PD). Although dopaminergic cell death in PD is associated with oxidative damage, the molecular mechanisms involved remain elusive. Glutaredoxins (GRXs) utilize the reducing power of glutathione to modulate redox-dependent signaling pathways by protein glutathionylation. We aimed to determine the role of GRX1 and protein glutathionylation in dopaminergic cell death. Results: In dopaminergic cells, toxicity induced by paraquat or 6-hydroxydopamine (6-OHDA) was inhibited by GRX1 overexpression, while its knock-down sensitized cells to paraquat-induced cell death. Dopaminergic cell death was paralleled by protein deglutathionylation, and this was reversed by GRX1. Mass spectrometry analysis of immunoprecipitated glutathionylated proteins identified the actin binding flightless-1 homolog protein (FLI-I) and the RalBP1-associated Eps domain-containing protein 2 (REPS2/POB1) as targets of glutathionylation in dopaminergic cells. Paraquat induced the degradation of FLI-I and REPS2 proteins, which corresponded with the activation of caspase 3 and cell death progression. GRX1 overexpression reduced both the degradation and deglutathionylation of FLI-I and REPS2, while stable overexpression of REPS2 reduced paraquat toxicity. A decrease in glutathionylated proteins and REPS2 levels was also observed in the substantia nigra of mice treated with paraquat. Innovation: We have identified novel protein targets of glutathionylation in dopaminergic cells and demonstrated the protective role of GRX1-mediated protein glutathionylation against paraquat-induced toxicity. Conclusions: These results demonstrate a protective role for GRX1 and increased protein glutathionylation in dopaminergic cell death induced by paraquat, and identify a novel protective role for REPS2.

UR - http://www.scopus.com/inward/record.url?scp=84867718174&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867718174&partnerID=8YFLogxK

U2 - 10.1089/ars.2011.4474

DO - 10.1089/ars.2011.4474

M3 - Article

C2 - 22816731

AN - SCOPUS:84867718174

VL - 17

SP - 1676

EP - 1693

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 12

ER -