title: Coupling endoplasmic reticulum stress to the cell death program in dopaminergic cells: effect of paraquat.
abstract: Parkinson's disease (PD) features oxidative stress and accumulation of misfolded (unfolded, alternatively folded, or mutant) proteins with associated loss of dopaminergic neurons. Oxidative stress and the accumulated misfolded proteins elicit cellular responses that include an endoplasmic reticulum (ER) stress response that may protect cells against the toxic buildup of misfolded proteins. Chronic ER stress and accumulation of misfolded proteins in excessive amounts, however, overwhelm the cellular 'quality control' system and impair the protective mechanisms designed to promote correct folding and degrade faulty proteins, ultimately leading to organelle dysfunction and neuronal cell death. Paraquat belongs to a class of bipyridyl herbicides and triggers oxidative stress and dopaminergic cell death. Epidemiological studies suggest an increased risk for developing PD following chronic exposure to paraquat. The present study was carried out to determine the role of paraquat in triggering cellular stress particularly ER stress and to elucidate the pathways that couple ER stress to dopaminergic cell death. We demonstrate that paraquat triggers ER stress, cell dysfunction, and dopaminergic cell death. p23, a small co-chaperone protein, is cleaved during ER stress-induced cell death triggered by paraquat and blockage of the caspase cleavage site of p23 was associated with decreased cell death. Paraquat also inhibits proteasomal activity that may further trigger accumulation of misfolded proteins resulting in ER stress. Our results indicate a protective role for p23 in PD-related programmed cell death. The data also underscore the involvement of ER, caspases, and the proteasomal system in ER stress-induced cell death process.
authors.affiliation: The Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Shankar J
authors.initials: SJ
authors.lastname: Chinta
authors.forename: Anand
authors.initials: A
authors.lastname: Rane
authors.forename: Karen S
authors.initials: KS
authors.lastname: Poksay
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen
authors.forename: Rammohan V
authors.initials: RV
authors.lastname: Rao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D019610:Cytoprotection / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006540:Herbicides / Q000633:toxicity; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D000071876:Prostaglandin-E Synthases; D017510:Protein Folding / Q000187:drug effects; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D006540:Herbicides; D018832:Molecular Chaperones; D020169:Caspases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D010269:Paraquat; D004298:Dopamine
references.citation: Neurosci Lett. 2002 Nov 15;333(1):25-8
references.pmid: 12401552
references.citation: Nature. 2003 Dec 18;426(6968):891-4
references.pmid: 14685249
references.citation: Nature. 1997 Aug 28;388(6645):839-40
references.pmid: 9278044
references.citation: Hum Mol Genet. 2005 Dec 15;14(24):3801-11
references.pmid: 16239241
references.citation: J Toxicol Environ Health A. 2007 Nov;70(21):1849-57
references.pmid: 17934957
references.citation: Nature. 2006 May 25;441(7092):513-7
references.pmid: 16724068
references.citation: FEBS Lett. 2002 Mar 13;514(2-3):122-8
references.pmid: 11943137
references.citation: Trends Cell Biol. 2004 Jan;14(1):20-8
references.pmid: 14729177
references.citation: Anticancer Agents Med Chem. 2007 May;7(3):359-65
references.pmid: 17504161
references.citation: Nat Rev Mol Cell Biol. 2007 May;8(5):405-13
references.pmid: 17377525
references.citation: Science. 1997 Jun 27;276(5321):2045-7
references.pmid: 9197268
references.citation: J Biol Chem. 2008 Feb 8;283(6):3357-3364
references.pmid: 18056701
references.citation: Free Radic Biol Med. 2006 Nov 1;41(9):1442-8
references.pmid: 17023271
references.citation: Science. 2005 Feb 11;307(5711):935-9
references.pmid: 15705855
references.citation: Exp Cell Res. 2008 Mar 10;314(5):950-60
references.pmid: 18255062
references.citation: Cell Death Differ. 2004 Apr;11(4):372-80
references.pmid: 14765132
references.citation: J Biol Chem. 2004 Jan 2;279(1):177-87
references.pmid: 14561754
references.citation: J Biol Chem. 2003 May 23;278(21):19367-77
references.pmid: 12598533
references.citation: Neurobiol Dis. 2004 Nov;17(2):250-9
references.pmid: 15474362
references.citation: Curr Opin Cell Biol. 2004 Dec;16(6):653-62
references.pmid: 15530777
references.citation: J Biol Chem. 2004 Oct 29;279(44):45495-502
references.pmid: 15322075
references.citation: J Toxicol Environ Health A. 2008;71(4):289-99
references.pmid: 18253895
references.citation: Neurobiol Aging. 2007 Jun;28(6):907-13
references.pmid: 16765489
references.citation: Neurochem Res. 1996 May;21(5):619-27
references.pmid: 8726972
references.citation: Nat Med. 2004 Jul;10 Suppl:S18-25
references.pmid: 15298006
references.citation: Nat Genet. 1998 Feb;18(2):106-8
references.pmid: 9462735
references.citation: J Biol Chem. 2004 Jul 30;279(31):32626-32
references.pmid: 15155744
references.citation: FASEB J. 2004 Jun;18(9):940-7
references.pmid: 15173105
references.citation: Nature. 1994 Sep 22;371(6495):346-7
references.pmid: 8090205
references.citation: Apoptosis. 2003 Aug;8(4):345-52
references.pmid: 12815277
references.citation: Science. 1997 Dec 12;278(5345):1966-8
references.pmid: 9395403
references.citation: Mech Ageing Dev. 2000 Sep 1;118(1-2):15-22
references.pmid: 10989121
references.citation: J Neurosci. 2002 Dec 15;22(24):10690-8
references.pmid: 12486162
references.citation: J Toxicol Environ Health A. 2005 Nov 26;68(22):1939-61
references.pmid: 16263688
references.citation: Mol Cell Biol. 1994 Mar;14(3):1956-63
references.pmid: 8114727
references.citation: J Neurochem. 2005 May;93(4):1030-7
references.pmid: 15857406
references.citation: Neuromolecular Med. 2003;4(1-2):21-36
references.pmid: 14528050
references.citation: J Neurochem. 2001 Nov;79(4):719-25
references.pmid: 11723164
references.citation: Brain Res. 2004 Oct 1;1022(1-2):164-72
references.pmid: 15353226
references.citation: Nature. 2006 Oct 19;443(7113):796-802
references.pmid: 17051206
references.citation: J Biol Chem. 1997 Apr 4;272(14):9086-92
references.pmid: 9083035
references.citation: Am J Physiol Renal Physiol. 2006 Sep;291(3):F578-87
references.pmid: 16622172
references.citation: Neurobiol Dis. 2002 Jul;10(2):119-27
references.pmid: 12127150
references.citation: Trends Cell Biol. 2000 Dec;10(12):524-30
references.pmid: 11121744
references.citation: Cell Death Differ. 2006 Mar;13(3):415-25
references.pmid: 16195741
references.citation: Exp Neurol. 1999 Feb;155(2):302-14
references.pmid: 10072306
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1265-70
references.pmid: 9448320
references.citation: J Biol Chem. 2005 Aug 12;280(32):29194-8
references.pmid: 15946937
references.citation: Neurotox Res. 2003;5(5):307-13
references.pmid: 14715449
references.citation: Antioxid Redox Signal. 2007 May;9(5):553-61
references.pmid: 17465880
references.citation: Nature. 2002 Apr 18;416(6882):763-7
references.pmid: 11961560
references.citation: Mech Ageing Dev. 2001 Sep 30;122(14):1499-510
references.pmid: 11511392
references.citation: J Cell Physiol. 1992 Dec;153(3):575-82
references.pmid: 1332981
references.citation: Cancer Biol Ther. 2006 Jul;5(7):745-8
references.pmid: 16861900
references.citation: Int J Biochem Cell Biol. 2005 May;37(5):942-6
references.pmid: 15743669
references.citation: Trends Neurosci. 2003 Aug;26(8):407-10
references.pmid: 12900170
references.citation: J Neurosci. 2007 Jan 24;27(4):901-8
references.pmid: 17251432
references.citation: Cell Stress Chaperones. 2003 Summer;8(2):108-13
references.pmid: 14627195
references.citation: Free Radic Biol Med. 2006 May 1;40(9):1557-63
references.pmid: 16632116
references.citation: Ann N Y Acad Sci. 2003 Jun;991:101-6
references.pmid: 12846978
references.citation: Science. 1996 Dec 6;274(5293):1715-7
references.pmid: 8939863
references.citation: J Biol Chem. 1994 Oct 7;269(40):24989-93
references.pmid: 7929183
references.citation: Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):1997-2006
references.pmid: 17034345
references.citation: Cell Death Differ. 2006 Mar;13(3):385-92
references.pmid: 16397584
references.citation: Nat Med. 1998 Nov;4(11):1318-20
references.pmid: 9809558
references.citation: J Biol Chem. 2001 Sep 7;276(36):33869-74
references.pmid: 11448953
references.citation: Antioxid Redox Signal. 2008 Jan;10(1):87-101
references.pmid: 17961071
references.citation: Annu Rev Cell Dev Biol. 2002;18:575-99
references.pmid: 12142265
references.citation: J Neurochem. 2003 Apr;85(1):82-6
references.pmid: 12641729
references.citation: J Biol Chem. 1998 May 22;273(21):12858-62
references.pmid: 9582315
references.citation: J Biol Chem. 2002 Jun 14;277(24):21836-42
references.pmid: 11919205
references.citation: Free Radic Biol Med. 2008 May 15;44(10):1787-94
references.pmid: 18395015
references.citation: J Biol Chem. 1997 Aug 29;272(35):21751-9
references.pmid: 9268304
references.citation: Ann N Y Acad Sci. 2000;920:42-5
references.pmid: 11193175
references.citation: Brain Res. 2000 Jun 2;866(1-2):33-43
references.pmid: 10825478
references.citation: Cell. 1998 Aug 21;94(4):491-501
references.pmid: 9727492