title: The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease.
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.
authors.affiliation: Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China; Laboratory of Molecular Neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming 650500, China.
authors.forename: Xian-Si
authors.initials: XS
authors.lastname: Zeng
authors.affiliation: Laboratory of Molecular Neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming 650500, China.
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Jia
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Laboratory of Molecular Neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming 650500, China.
authors.forename: Sheng-Dong
authors.initials: SD
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming 650500, China. Electronic address: jiebai662001@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D016716:PC12 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047992:TNF Receptor-Associated Factor 2; C515559:Txn1 protein, mouse; C040846:4-phenyl-1,2,3,6-tetrahydropyridine; D051742:Transcription Factor CHOP; D013879:Thioredoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D004722:Endoribonucleases; D053454:Caspase 12; D015655:1-Methyl-4-phenylpyridinium
keywords: ER stress; Free radicals; MPP(+)/MPTP; Parkinson disease; Thioredoxin-1