Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults.
Parkinson's disease (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and alpha-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant alpha-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetylcysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant alpha-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD.
Liu
Fang
F
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Hindupur
Jagadish
J
Nguyen
Jamie L
JL
Ruf
Katie J
KJ
Zhu
Junyi
J
Schieler
Jeremy L
JL
Bonham
Connie C
CC
Wood
Karl V
KV
Davisson
V Jo
VJ
Rochet
Jean-Christophe
JC
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000633:toxicity; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051150:Methionine Sulfoxide Reductases; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000633:toxicity; D014810:Vitamin E / Q000494:pharmacology; D051844:alpha-Synuclein / Q000378:metabolism
D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C497604:SNCA protein, human; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D012402:Rotenone; D014810:Vitamin E; D010088:Oxidoreductases; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine; D000111:Acetylcysteine