Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons

Significance S-nitrosylation, addition of an NO group to a cysteine thiol, can regulate protein activity. Aberrant protein S-nitrosylation, however, can disrupt normal enzyme function, as is the case for S-nitrosylated peroxiredoxin (SNO-Prx), which would otherwise catabolize toxic peroxides that occur under neurodegenerative conditions such as Parkinson’s disease. Here, we describe a paradigm of N-phosphorylation–mediated denitrosylation by the enzyme sulfiredoxin that removes NO from Prx. The findings are at the center of redox control of the cell, explaining reactivation by sulfiredoxin of both Prx-SO2H and SNO-Prx and thus describe a master regulator of redox reactions that combats nitrosative and oxidative stress in cells. These results suggest that sulfiredoxin may be an important target for therapeutic intervention in neurodegenerative disorders. 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.