Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons.
Recent studies have pointed to protein S-nitrosylation as a critical regulator of cellular redox homeostasis. For example, S-nitrosylation of peroxiredoxin-2 (Prx2), a peroxidase widely expressed in mammalian neurons, inhibits both enzymatic activity and protective function against oxidative stress. Here, using in vitro and in vivo approaches, we identify a role and reaction mechanism of the reductase sulfiredoxin (Srxn1) as an enzyme that denitrosylates (thus removing -SNO) from Prx2 in an ATP-dependent manner. Accordingly, by decreasing S-nitrosylated Prx2 (SNO-Prx2), overexpression of Srxn1 protects dopaminergic neural cells and human-induced pluripotent stem cell (hiPSC)-derived neurons from NO-induced hypersensitivity to oxidative stress. The pathophysiological relevance of this observation is suggested by our finding that SNO-Prx2 is dramatically increased in murine and human Parkinson's disease (PD) brains. Our findings therefore suggest that Srxn1 may represent a therapeutic target for neurodegenerative disorders such as PD that involve nitrosative/oxidative stress.
Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
Carmen R
CR
Sunico
Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.|Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.
Abdullah
A
Sultan
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.
Tomohiro
T
Nakamura
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.
Nima
N
Dolatabadi
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.
James
J
Parker
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
Bing
B
Shan
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
Xuemei
X
Han
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
John R
JR
Yates
Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093.|Department of Pathology, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
Eliezer
E
Masliah
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.
Rajesh
R
Ambasudhan
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.
Nobuki
N
Nakanishi
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121; slipton@ucsd.edu.|Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Stuart A
SA
Lipton
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000737:chemistry; D018384:Oxidative Stress; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D054464:Peroxiredoxins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation
D009569:Nitric Oxide; D000255:Adenosine Triphosphate; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D050862:Oxidoreductases Acting on Sulfur Group Donors; C504024:SRXN1 protein, human
S-nitrosylation; denitrosylase; iPSC-derived dopaminergic neuron; peroxiredoxin; sulfiredoxin