S-nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson's disease.
Peroxiredoxins (Prx), a family of peroxidases that reduce intracellular peroxides with the thioredoxin system as the electron donor, are highly expressed in various cellular compartments. Among the antioxidant Prx enzymes, Prx2 is the most abundant in mammalian neurons, making it a prime candidate to defend against oxidative stress. Here we report that Prx2 is S-nitrosylated (forming SNO-Prx2) by reaction with nitric oxide at two critical cysteine residues (C51 and C172), preventing its reaction with peroxides. We observed increased SNO-Prx2 in human Parkinson's disease (PD) brains, and S-nitrosylation of Prx2 inhibited both its enzymatic activity and protective function from oxidative stress. Dopaminergic neurons, which are lost in PD, become particularly vulnerable. Thus, our data provide a direct link between nitrosative/oxidative stress and neurodegenerative disorders such as PD.
Fang
Jianguo
J
Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Nakamura
Tomohiro
T
Cho
Dong-Hyung
DH
Gu
Zezong
Z
Lipton
Stuart A
SA
D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002460:Cell Line; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D009589:Nitrogen Oxides / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*
D000975:Antioxidants; D009589:Nitrogen Oxides; D054464:Peroxiredoxins; D003545:Cysteine