title: S-nitrosylation of critical protein thiols mediates protein misfolding and mitochondrial dysfunction in neurodegenerative diseases.
abstract: Excessive nitrosative and oxidative stress is thought to trigger cellular signaling pathways leading to neurodegenerative conditions. Such redox dysregulation can result from many cellular events, including hyperactivation of the N-methyl-D-aspartate-type glutamate receptor, mitochondrial dysfunction, and cellular aging. Recently, we and our colleagues have shown that excessive generation of free radicals and related molecules, in particular nitric oxide species (NO), can trigger pathological production of misfolded proteins, abnormal mitochondrial dynamics (comprised of mitochondrial fission and fusion events), and apoptotic pathways in neuronal cells. Emerging evidence suggests that excessive NO production can contribute to these pathological processes, specifically by S-nitrosylation of specific target proteins. Here, we highlight examples of S-nitrosylated proteins that regulate misfolded protein accumulation and mitochondrial dynamics. For instance, in models of Parkinson's disease, these S-nitrosylation targets include parkin, a ubiquitin E3 ligase and neuroprotective molecule, and protein-disulfide isomerase, a chaperone enzyme for nascent protein folding. S-Nitrosylation of protein-disulfide isomerase may also be associated with mutant Cu/Zn superoxide dismutase toxicity in amyotrophic lateral sclerosis. Additionally, in models of Alzheimer's disease, excessive NO generation leads to the formation of S-nitrosylated dynamin-related protein 1 (forming SNO-Drp1), which contributes to abnormal mitochondrial fragmentation and resultant synaptic damage.
authors.affiliation: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019704:Protein Disulfide-Isomerases
references.citation: Mol Cell. 2008 Aug 22;31(4):586-597
references.pmid: 18722182
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10810-4
references.pmid: 15252205
references.citation: Science. 1997 Jun 27;276(5321):2045-7
references.pmid: 9197268
references.citation: Neurobiol Aging. 2006 Apr;27(4):524-9
references.pmid: 16213628
references.citation: Nature. 1998 Oct 1;395(6701):451-2
references.pmid: 9774100
references.citation: Trends Neurosci. 2002 Sep;25(9):474-80
references.pmid: 12183209
references.citation: Free Radic Biol Med. 2006 Nov 1;41(9):1442-8
references.pmid: 17023271
references.citation: J Biol Chem. 2004 Nov 12;279(46):47998-8003
references.pmid: 15326189
references.citation: Life Sci. 1999;65(18-19):1977-81
references.pmid: 10576449
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8
references.pmid: 18799731
references.citation: Neurobiol Dis. 2006 May;22(2):388-400
references.pmid: 16473015
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8
references.pmid: 16818890
references.citation: N Engl J Med. 1994 Mar 3;330(9):613-22
references.pmid: 7905600
references.citation: Brain. 2010 Jan;133(Pt 1):105-16
references.pmid: 19903735
references.citation: Science. 2003 Jan 10;299(5604):256-9
references.pmid: 12446870
references.citation: Biochemistry. 2007 Jun 26;46(25):7325-36
references.pmid: 17542619
references.citation: J Biol Chem. 2000 Mar 17;275(11):7918-24
references.pmid: 10713108
references.citation: EMBO J. 2006 Aug 9;25(15):3618-26
references.pmid: 16874301
references.citation: J Biol Chem. 2004 Nov 26;279(48):50286-94
references.pmid: 15364948
references.citation: Nature. 1988 Nov 24;336(6197):385-8
references.pmid: 2904125
references.citation: Biochemistry. 1991 Jan 22;30(3):613-9
references.pmid: 1988050
references.citation: J Neurosci. 2009 Nov 4;29(44):13850-9
references.pmid: 19889996
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162-6
references.pmid: 7638161
references.citation: Science. 2004 May 28;304(5675):1328-31
references.pmid: 15105460
references.citation: Annu Rev Biochem. 2005;74:29-52
references.pmid: 15952880
references.citation: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):562-6
references.pmid: 16584707
references.citation: J Neurochem. 2006 Jun;97(6):1611-26
references.pmid: 16805772
references.citation: J Biol Chem. 2006 Oct 6;281(40):30152-65
references.pmid: 16847061
references.citation: Brain Res Mol Brain Res. 2005 Mar 24;134(1):84-102
references.pmid: 15790533
references.citation: J Biol Chem. 2004 Dec 24;279(52):54558-66
references.pmid: 15485869
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2169-74
references.pmid: 18250306
references.citation: J Biol Chem. 2009 Aug 21;284(34):22938-51
references.pmid: 19546216
references.citation: Brain Res Rev. 2009 Jun;61(1):33-48
references.pmid: 19394359
references.citation: J Neurosci. 2005 Feb 23;25(8):2002-9
references.pmid: 15728840
references.citation: Biochem Biophys Res Commun. 2006 Jan 13;339(2):667-72
references.pmid: 16316629
references.citation: Nat Cell Biol. 2005 Jul;7(7):665-74
references.pmid: 15951807
references.citation: Science. 2003 Feb 7;299(5608):896-9
references.pmid: 12574632
references.citation: Cell Death Differ. 2003 Jul;10(7):757-60
references.pmid: 12815458
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1295-300
references.pmid: 16432212
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
references.pmid: 18230723
references.citation: Hum Mol Genet. 2005 Oct 1;14(19):2871-80
references.pmid: 16115812
references.citation: J Biol Chem. 2004 Aug 20;279(34):35967-74
references.pmid: 15208300
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4854-9
references.pmid: 15781872
references.citation: J Neurosci. 2001 May 1;21(9):3017-23
references.pmid: 11312286
references.citation: Nat Rev Neurosci. 2001 May;2(5):325-34
references.pmid: 11331916
references.citation: ACS Chem Biol. 2006 Jul 21;1(6):355-8
references.pmid: 17163772
references.citation: Neuron. 2004 Nov 18;44(4):595-600
references.pmid: 15541308
references.citation: Biochem J. 2006 Mar 15;394(Pt 3):627-34
references.pmid: 16371007
references.citation: Cell. 2001 Sep 21;106(6):675-83
references.pmid: 11572774
references.citation: Nat Med. 2009 Dec;15(12):1407-13
references.pmid: 19915593
references.citation: EMBO J. 2003 Oct 15;22(20):5435-45
references.pmid: 14532116
references.citation: Nat Rev Neurosci. 2004 Oct;5(10):771-81
references.pmid: 15378037
references.citation: Neuron. 2007 Jan 4;53(1):53-64
references.pmid: 17196530
references.citation: J Biol Chem. 2006 Apr 14;281(15):10056-65
references.pmid: 16481325
references.citation: J Neurochem. 2009 May;109 Suppl 1:153-9
references.pmid: 19393022
references.citation: Science. 2002 Aug 16;297(5584):1186-90
references.pmid: 12183632
references.citation: J Am Chem Soc. 2003 Jun 11;125(23):6972-6
references.pmid: 12783550
references.citation: Nat Genet. 2006 Oct;38(10):1184-91
references.pmid: 16964263
references.citation: Science. 1998 Jan 9;279(5348):234-7
references.pmid: 9422697
references.citation: Cell Mol Life Sci. 1999 Jul;55(8-9):1015-28
references.pmid: 10484661
references.citation: Nature. 1993 Aug 12;364(6438):626-32
references.pmid: 8394509
references.citation: Brain Res. 2004 Oct 1;1022(1-2):164-72
references.pmid: 15353226
references.citation: Science. 2000 Nov 3;290(5493):985-9
references.pmid: 11062131
references.citation: J Neurosci. 2009 Jul 15;29(28):9090-103
references.pmid: 19605646
references.citation: Neuron. 2004 Nov 18;44(4):601-7
references.pmid: 15541309
references.citation: J Neurosci. 1998 Mar 15;18(6):2161-73
references.pmid: 9482801
references.citation: Nature. 1984 May 17-23;309(5965):261-3
references.pmid: 6325946
references.citation: Science. 1969 May 9;164(3880):719-21
references.pmid: 5778021
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7631-6
references.pmid: 9636201
references.citation: EMBO Rep. 2007 Oct;8(10):939-44
references.pmid: 17721437
references.citation: Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7105-9
references.pmid: 7624378
references.citation: Nat Cell Biol. 2010 Feb;12(2):119-31
references.pmid: 20098416
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):6161-6
references.pmid: 10811898
references.citation: Curr Opin Cell Biol. 2006 Aug;18(4):453-9
references.pmid: 16781135
references.citation: Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10769-72
references.pmid: 7504282
references.citation: Nat Neurosci. 2002 Aug;5(8):731-6
references.pmid: 12089530
references.citation: Cell Death Differ. 2007 Mar;14(3):462-71
references.pmid: 17053808
references.citation: Cell Death Differ. 2009 Jun;16(6):899-909
references.pmid: 19300456
references.citation: J Biol Chem. 2005 Apr 29;280(17):17266-74
references.pmid: 15691826
references.citation: Nat Genet. 2000 Oct;26(2):207-10
references.pmid: 11017079
references.citation: Curr Opin Chem Biol. 2000 Dec;4(6):687-95
references.pmid: 11102875
references.citation: J Neurosci. 2007 Nov 7;27(45):12413-8
references.pmid: 17989306
references.citation: Hum Mol Genet. 2009 Feb 15;18(4):737-52
references.pmid: 19039036
references.citation: J Biol Chem. 2007 Jul 27;282(30):21583-7
references.pmid: 17553808
references.citation: Nature. 2006 May 25;441(7092):513-7
references.pmid: 16724068
references.citation: Nat Rev Mol Cell Biol. 2005 Feb;6(2):150-66
references.pmid: 15688001
references.citation: Neurobiol Aging. 2006 Jul;27(7):973-82
references.pmid: 15964666
references.citation: J Neurosci. 2007 Dec 19;27(51):13997-4006
references.pmid: 18094238
references.citation: J Biol Chem. 2003 Feb 21;278(8):5984-92
references.pmid: 12458194
references.citation: Nature. 2009 Feb 19;457(7232):981-9
references.pmid: 19225519
references.citation: Science. 2005 Jun 24;308(5730):1870; author reply 1870
references.pmid: 15976289
references.citation: FASEB J. 1998 Jul;12(10):773-90
references.pmid: 9657518
references.citation: Ann Neurol. 2004 Jul;56(1):149-62
references.pmid: 15236415
references.citation: J Cell Biol. 2007 Jul 2;178(1):71-84
references.pmid: 17606867
references.citation: Nat Neurosci. 2000 Jan;3(1):15-21
references.pmid: 10607390
references.citation: Nature. 1998 Apr 9;392(6676):605-8
references.pmid: 9560156
references.citation: Nat Rev Neurosci. 2007 Oct;8(10):803-8
references.pmid: 17882256
references.citation: Nature. 2006 Dec 7;444(7120):766-9
references.pmid: 17122778
references.citation: Science. 1999 Jun 11;284(5421):1845-8
references.pmid: 10364559
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83
references.pmid: 12642658
references.citation: Science. 2009 Apr 3;324(5923):102-5
references.pmid: 19342591
references.citation: J Cell Sci. 2007 Feb 1;120(Pt 3):492-501
references.pmid: 17251380
references.citation: J Biol Chem. 2006 Sep 22;281(38):27916-23
references.pmid: 16870617
references.citation: Trends Cell Biol. 2004 Dec;14(12):703-11
references.pmid: 15564047
references.citation: Ann Neurol. 1998 Sep;44(3 Suppl 1):S110-4
references.pmid: 9749581
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2404-9
references.pmid: 16461917
references.citation: Exp Neurol. 2009 Aug;218(2):247-56
references.pmid: 19332061
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
references.pmid: 19050078
references.citation: Neurosci Lett. 2002 Dec 16;334(3):196-200
references.pmid: 12453628
references.citation: Neuron. 1995 Oct;15(4):961-73
references.pmid: 7576644
references.citation: J Cell Biol. 2007 May 7;177(3):439-50
references.pmid: 17470634
references.citation: Neurology. 1994 Jun;44(6):1090-6
references.pmid: 8208407
references.citation: Ann Neurol. 1999 Jan;45(1):25-32
references.pmid: 9894873
references.citation: Science. 2004 May 21;304(5674):1158-60
references.pmid: 15087508
references.citation: Cell. 2004 Dec 17;119(6):873-87
references.pmid: 15607982
references.citation: Neuron. 2003 Oct 9;40(2):427-46
references.pmid: 14556719
references.citation: J Biol Chem. 2004 Apr 9;279(15):15499-504
references.pmid: 14734542
references.citation: Nat Neurosci. 2008 Apr;11(4):476-87
references.pmid: 18344994
references.citation: Nature. 1991 Jun 27;351(6329):714-8
references.pmid: 1712077
references.citation: J Biol Chem. 2007 Apr 13;282(15):11521-9
references.pmid: 17301055
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6025-30
references.pmid: 16595634
references.citation: Science. 2002 Feb 1;295(5556):865-8
references.pmid: 11823645
references.citation: Nat Neurosci. 2009 Jul;12(7):857-63
references.pmid: 19503084
references.citation: Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
references.pmid: 16025099
references.citation: J Alzheimers Dis. 2006 Jul;9(2):119-26
references.pmid: 16873959
references.citation: Neurochem Res. 2010 Aug;35(8):1206-13
references.pmid: 20455021
references.citation: J Biol Chem. 2009 May 15;284(20):13843-13855
references.pmid: 19279012
references.citation: J Neurochem. 2005 Mar;92(5):1091-103
references.pmid: 15715660
references.citation: J Neurochem. 2008 Jan;104(2):420-34
references.pmid: 17953654
references.citation: FEBS Lett. 1994 May 23;345(1):50-4
references.pmid: 8194600
references.citation: Neuron. 2009 Jun 25;62(6):788-801
references.pmid: 19555648
references.citation: J Neurosci. 2005 Mar 16;25(11):2793-802
references.pmid: 15772339
references.citation: EMBO J. 2006 Aug 23;25(16):3900-11
references.pmid: 16874299
references.citation: Nat Genet. 2004 May;36(5):449-51
references.pmid: 15064763
references.citation: J Neurosci. 2006 Oct 18;26(42):10636-45
references.pmid: 17050703
references.citation: EMBO Rep. 2006 Oct;7(10):1019-22
references.pmid: 16936636
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5018-23
references.pmid: 20194754
references.citation: Hum Genet. 2005 Jan;116(1-2):23-7
references.pmid: 15549395
references.citation: Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6368-71
references.pmid: 1648740
references.citation: Nat Rev Neurosci. 2005 Jan;6(1):11-22
references.pmid: 15611723
references.citation: J Biol Chem. 2009 Jul 10;284(28):18754-66
references.pmid: 19389700
references.citation: N Engl J Med. 2007 Apr 26;356(17):1736-41
references.pmid: 17460227
references.citation: Eur J Neurosci. 2005 Nov;22(9):2376-80
references.pmid: 16262676
references.citation: Nat Neurosci. 2000 Dec;3(12):1301-6
references.pmid: 11100151
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9
references.pmid: 16432136
references.citation: Neuroscience. 2010 Apr 28;167(1):68-87
references.pmid: 20096331
references.citation: Mol Biol Evol. 2002 Dec;19(12):2039-50
references.pmid: 12446796
references.citation: EMBO J. 2007 Jan 24;26(2):559-66
references.pmid: 17170701
references.citation: Nat Rev Drug Discov. 2006 Feb;5(2):160-70
references.pmid: 16424917