Abstract
Endoplasmic reticulum (ER) stress has been implicated in Parkinson disease. We previously reported that thioredoxin 1 (Trx-1) suppressed the ER stress caused by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine; however, its molecular mechanism remains largely unknown. In the present study, we showed that 1-methyl-4-phenylpyridinium ion (MPP(+)) induced ER stress by activating glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2 (TRAF2), c-Jun N-terminal kinase (JNK), caspase-12, and C/EBP homologous protein (CHOP) in PC12 cells. The downregulation of Trx-1 aggravated the ER stress and further increased the expression of the above molecules induced by MPP(+). In contrast, overexpression of Trx-1 attenuated the ER stress and repressed the expression of the above molecules induced by MPP(+). More importantly, the overexpression of Trx-1 in transgenic mice suppressed ER stress by inhibiting the activation of these molecules. We present, for the first time, the molecular mechanism of Trx-1 suppression of endoplasmic reticulum stress in Parkinson disease in vitro and in vivo. Based on our findings, we conclude that Trx-1 plays a neuroprotective role in Parkinson disease by suppressing ER stress by regulating the activation of GRP78, IRE1α, TRAF2, JNK, caspase-12, and CHOP.
Keywords:
ER stress; Free radicals; MPP(+)/MPTP; Parkinson disease; Thioredoxin-1.
Crown Copyright © 2013 Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / analogs & derivatives
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
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1-Methyl-4-phenylpyridinium / pharmacology
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Animals
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Caspase 12 / genetics
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Caspase 12 / metabolism
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects
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Endoplasmic Reticulum Stress / genetics*
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Endoribonucleases / genetics
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Endoribonucleases / metabolism
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Gene Expression Regulation
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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MPTP Poisoning / chemically induced
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MPTP Poisoning / genetics*
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MPTP Poisoning / metabolism
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MPTP Poisoning / physiopathology
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Mice
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Mice, Transgenic
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PC12 Cells
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Signal Transduction
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TNF Receptor-Associated Factor 2 / genetics
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TNF Receptor-Associated Factor 2 / metabolism
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Thioredoxins / genetics*
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Thioredoxins / metabolism
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism
Substances
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Ddit3 protein, mouse
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Endoplasmic Reticulum Chaperone BiP
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Heat-Shock Proteins
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Hspa5 protein, mouse
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TNF Receptor-Associated Factor 2
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Txn1 protein, mouse
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4-phenyl-1,2,3,6-tetrahydropyridine
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Transcription Factor CHOP
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Thioredoxins
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Ern1 protein, mouse
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Protein Serine-Threonine Kinases
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MAP Kinase Kinase 4
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Endoribonucleases
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Caspase 12
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1-Methyl-4-phenylpyridinium