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The Nrf2/SKN-1-dependent glutathione S-transferase π homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism.
- Source :
-
Neurotoxicology [Neurotoxicology] 2013 Sep; Vol. 38, pp. 51-60. Date of Electronic Publication: 2013 May 27. - Publication Year :
- 2013
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Abstract
- Exposure to high levels of manganese (Mn) results in a neurological condition termed manganism, which is characterized by oxidative stress, abnormal dopamine (DA) signaling, and cell death. Epidemiological evidence suggests correlations with occupational exposure to Mn and the development of the movement disorder Parkinson's disease (PD), yet the molecular determinants common between the diseases are ill-defined. Glutathione S-transferases (GSTs) of the class pi (GSTπ) are phase II detoxification enzymes that conjugate both endogenous and exogenous compounds to glutathione to reduce cellular oxidative stress, and their decreased expression has recently been implicated in PD progression. In this study we demonstrate that a Caenorhabditis elegans GSTπ homologue, GST-1, inhibits Mn-induced DA neuron degeneration. We show that GST-1 is expressed in DA neurons, Mn induces GST-1 gene and protein expression, and GST-1-mediated neuroprotection is dependent on the PD-associated transcription factor Nrf2/SKN-1, as a reduction in SKN-1 gene expression results in a decrease in GST-1 protein expression and an increase in DA neuronal death. Furthermore, decreases in gene expression of the SKN-1 inhibitor WDR-23 or the GSTπ-binding cell death activator JNK/JNK-1 result in an increase in resistance to the metal. Finally, we show that the Mn-induced DA neuron degeneration is independent of the dopamine transporter DAT, but is largely dependent on the caspases CED-3 and the novel caspase CSP-1. This study identifies a C. elegans Nrf2/SKN-1-dependent GSTπ homologue, cell death effectors of GSTπ-associated xenobiotic-induced pathology, and provides the first in vivo evidence that a phase II detoxification enzyme may modulate DA neuron vulnerability in manganism.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Caenorhabditis elegans cytology
Caenorhabditis elegans enzymology
Caenorhabditis elegans Proteins genetics
Caspases genetics
Caspases metabolism
Disease Models, Animal
Dopamine Plasma Membrane Transport Proteins genetics
Gene Expression
Glutathione S-Transferase pi biosynthesis
Glutathione S-Transferase pi genetics
Mitogen-Activated Protein Kinases genetics
Repressor Proteins genetics
Caenorhabditis elegans metabolism
Caenorhabditis elegans Proteins metabolism
DNA-Binding Proteins metabolism
Dopaminergic Neurons enzymology
Dopaminergic Neurons pathology
Glutathione S-Transferase pi metabolism
Manganese Poisoning enzymology
Manganese Poisoning pathology
Nerve Degeneration prevention & control
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9711
- Volume :
- 38
- Database :
- MEDLINE
- Journal :
- Neurotoxicology
- Publication Type :
- Academic Journal
- Accession number :
- 23721876
- Full Text :
- https://doi.org/10.1016/j.neuro.2013.05.014