S-nitrosylation of critical protein thiols mediates protein misfolding and mitochondrial dysfunction in neurodegenerative diseases.
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.
Nakamura
Tomohiro
T
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.
Lipton
Stuart A
SA
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*
D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019704:Protein Disulfide-Isomerases
Mol Cell. 2008 Aug 22;31(4):586-597
18722182
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10810-4
15252205
Science. 1997 Jun 27;276(5321):2045-7
9197268
Neurobiol Aging. 2006 Apr;27(4):524-9
16213628
Nature. 1998 Oct 1;395(6701):451-2
9774100
Trends Neurosci. 2002 Sep;25(9):474-80
12183209
Free Radic Biol Med. 2006 Nov 1;41(9):1442-8
17023271
J Biol Chem. 2004 Nov 12;279(46):47998-8003
15326189
Life Sci. 1999;65(18-19):1977-81
10576449
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8
18799731
Neurobiol Dis. 2006 May;22(2):388-400
16473015
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8
16818890
N Engl J Med. 1994 Mar 3;330(9):613-22
7905600
Brain. 2010 Jan;133(Pt 1):105-16
19903735
Science. 2003 Jan 10;299(5604):256-9
12446870
Biochemistry. 2007 Jun 26;46(25):7325-36
17542619
J Biol Chem. 2000 Mar 17;275(11):7918-24
10713108
EMBO J. 2006 Aug 9;25(15):3618-26
16874301
J Biol Chem. 2004 Nov 26;279(48):50286-94
15364948
Nature. 1988 Nov 24;336(6197):385-8
2904125
Biochemistry. 1991 Jan 22;30(3):613-9
1988050
J Neurosci. 2009 Nov 4;29(44):13850-9
19889996
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162-6
7638161
Science. 2004 May 28;304(5675):1328-31
15105460
Annu Rev Biochem. 2005;74:29-52
15952880
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):562-6
16584707
J Neurochem. 2006 Jun;97(6):1611-26
16805772
J Biol Chem. 2006 Oct 6;281(40):30152-65
16847061
Brain Res Mol Brain Res. 2005 Mar 24;134(1):84-102
15790533
J Biol Chem. 2004 Dec 24;279(52):54558-66
15485869
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2169-74
18250306
J Biol Chem. 2009 Aug 21;284(34):22938-51
19546216
Brain Res Rev. 2009 Jun;61(1):33-48
19394359
J Neurosci. 2005 Feb 23;25(8):2002-9
15728840
Biochem Biophys Res Commun. 2006 Jan 13;339(2):667-72
16316629
Nat Cell Biol. 2005 Jul;7(7):665-74
15951807
Science. 2003 Feb 7;299(5608):896-9
12574632
Cell Death Differ. 2003 Jul;10(7):757-60
12815458
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1295-300
16432212
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
18230723
Hum Mol Genet. 2005 Oct 1;14(19):2871-80
16115812
J Biol Chem. 2004 Aug 20;279(34):35967-74
15208300
Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4854-9
15781872
J Neurosci. 2001 May 1;21(9):3017-23
11312286
Nat Rev Neurosci. 2001 May;2(5):325-34
11331916
ACS Chem Biol. 2006 Jul 21;1(6):355-8
17163772
Neuron. 2004 Nov 18;44(4):595-600
15541308
Biochem J. 2006 Mar 15;394(Pt 3):627-34
16371007
Cell. 2001 Sep 21;106(6):675-83
11572774
Nat Med. 2009 Dec;15(12):1407-13
19915593
EMBO J. 2003 Oct 15;22(20):5435-45
14532116
Nat Rev Neurosci. 2004 Oct;5(10):771-81
15378037
Neuron. 2007 Jan 4;53(1):53-64
17196530
J Biol Chem. 2006 Apr 14;281(15):10056-65
16481325
J Neurochem. 2009 May;109 Suppl 1:153-9
19393022
Science. 2002 Aug 16;297(5584):1186-90
12183632
J Am Chem Soc. 2003 Jun 11;125(23):6972-6
12783550
Nat Genet. 2006 Oct;38(10):1184-91
16964263
Science. 1998 Jan 9;279(5348):234-7
9422697
Cell Mol Life Sci. 1999 Jul;55(8-9):1015-28
10484661
Nature. 1993 Aug 12;364(6438):626-32
8394509
Brain Res. 2004 Oct 1;1022(1-2):164-72
15353226
Science. 2000 Nov 3;290(5493):985-9
11062131
J Neurosci. 2009 Jul 15;29(28):9090-103
19605646
Neuron. 2004 Nov 18;44(4):601-7
15541309
J Neurosci. 1998 Mar 15;18(6):2161-73
9482801
Nature. 1984 May 17-23;309(5965):261-3
6325946
Science. 1969 May 9;164(3880):719-21
5778021
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7631-6
9636201
EMBO Rep. 2007 Oct;8(10):939-44
17721437
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7105-9
7624378
Nat Cell Biol. 2010 Feb;12(2):119-31
20098416
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6161-6
10811898
Curr Opin Cell Biol. 2006 Aug;18(4):453-9
16781135
Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10769-72
7504282
Nat Neurosci. 2002 Aug;5(8):731-6
12089530
Cell Death Differ. 2007 Mar;14(3):462-71
17053808
Cell Death Differ. 2009 Jun;16(6):899-909
19300456
J Biol Chem. 2005 Apr 29;280(17):17266-74
15691826
Nat Genet. 2000 Oct;26(2):207-10
11017079
Curr Opin Chem Biol. 2000 Dec;4(6):687-95
11102875
J Neurosci. 2007 Nov 7;27(45):12413-8
17989306
Hum Mol Genet. 2009 Feb 15;18(4):737-52
19039036
J Biol Chem. 2007 Jul 27;282(30):21583-7
17553808
Nature. 2006 May 25;441(7092):513-7
16724068
Nat Rev Mol Cell Biol. 2005 Feb;6(2):150-66
15688001
Neurobiol Aging. 2006 Jul;27(7):973-82
15964666
J Neurosci. 2007 Dec 19;27(51):13997-4006
18094238
J Biol Chem. 2003 Feb 21;278(8):5984-92
12458194
Nature. 2009 Feb 19;457(7232):981-9
19225519
Science. 2005 Jun 24;308(5730):1870; author reply 1870
15976289
FASEB J. 1998 Jul;12(10):773-90
9657518
Ann Neurol. 2004 Jul;56(1):149-62
15236415
J Cell Biol. 2007 Jul 2;178(1):71-84
17606867
Nat Neurosci. 2000 Jan;3(1):15-21
10607390
Nature. 1998 Apr 9;392(6676):605-8
9560156
Nat Rev Neurosci. 2007 Oct;8(10):803-8
17882256
Nature. 2006 Dec 7;444(7120):766-9
17122778
Science. 1999 Jun 11;284(5421):1845-8
10364559
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83
12642658
Science. 2009 Apr 3;324(5923):102-5
19342591
J Cell Sci. 2007 Feb 1;120(Pt 3):492-501
17251380
J Biol Chem. 2006 Sep 22;281(38):27916-23
16870617
Trends Cell Biol. 2004 Dec;14(12):703-11
15564047
Ann Neurol. 1998 Sep;44(3 Suppl 1):S110-4
9749581
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2404-9
16461917
Exp Neurol. 2009 Aug;218(2):247-56
19332061
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
19050078
Neurosci Lett. 2002 Dec 16;334(3):196-200
12453628
Neuron. 1995 Oct;15(4):961-73
7576644
J Cell Biol. 2007 May 7;177(3):439-50
17470634
Neurology. 1994 Jun;44(6):1090-6
8208407
Ann Neurol. 1999 Jan;45(1):25-32
9894873
Science. 2004 May 21;304(5674):1158-60
15087508
Cell. 2004 Dec 17;119(6):873-87
15607982
Neuron. 2003 Oct 9;40(2):427-46
14556719
J Biol Chem. 2004 Apr 9;279(15):15499-504
14734542
Nat Neurosci. 2008 Apr;11(4):476-87
18344994
Nature. 1991 Jun 27;351(6329):714-8
1712077
J Biol Chem. 2007 Apr 13;282(15):11521-9
17301055
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6025-30
16595634
Science. 2002 Feb 1;295(5556):865-8
11823645
Nat Neurosci. 2009 Jul;12(7):857-63
19503084
Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
16025099
J Alzheimers Dis. 2006 Jul;9(2):119-26
16873959
Neurochem Res. 2010 Aug;35(8):1206-13
20455021
J Biol Chem. 2009 May 15;284(20):13843-13855
19279012
J Neurochem. 2005 Mar;92(5):1091-103
15715660
J Neurochem. 2008 Jan;104(2):420-34
17953654
FEBS Lett. 1994 May 23;345(1):50-4
8194600
Neuron. 2009 Jun 25;62(6):788-801
19555648
J Neurosci. 2005 Mar 16;25(11):2793-802
15772339
EMBO J. 2006 Aug 23;25(16):3900-11
16874299
Nat Genet. 2004 May;36(5):449-51
15064763
J Neurosci. 2006 Oct 18;26(42):10636-45
17050703
EMBO Rep. 2006 Oct;7(10):1019-22
16936636
Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5018-23
20194754
Hum Genet. 2005 Jan;116(1-2):23-7
15549395
Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6368-71
1648740
Nat Rev Neurosci. 2005 Jan;6(1):11-22
15611723
J Biol Chem. 2009 Jul 10;284(28):18754-66
19389700
N Engl J Med. 2007 Apr 26;356(17):1736-41
17460227
Eur J Neurosci. 2005 Nov;22(9):2376-80
16262676
Nat Neurosci. 2000 Dec;3(12):1301-6
11100151
Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9
16432136
Neuroscience. 2010 Apr 28;167(1):68-87
20096331
Mol Biol Evol. 2002 Dec;19(12):2039-50
12446796
EMBO J. 2007 Jan 24;26(2):559-66
17170701
Nat Rev Drug Discov. 2006 Feb;5(2):160-70
16424917