title: Peroxiredoxin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade.
abstract: The peroxiredoxin (PRX) family of antioxidant enzymes helps maintain the intracellular reducing milieu and suppresses apoptosis in non-neuronal cells. However, whether PRX can inhibit neuronal apoptosis through specific signaling mechanisms remains poorly understood. Induction of PRX2, the most abundant neuronal PRX, occurs in Parkinson's disease (PD) patient brains, but its functional impact is unclear. In the present study, we used the dopaminergic (DA) toxin 6-hydroxydopamine (6-OHDA) to model PD and explore the protective effect and mechanisms of PRX on DA neurons. Of the 2-cysteine PRXs that were tested in MN9D DA neurons, endogenous PRX2 was most beneficial to cell survival. Lentivirus-mediated PRX2 overexpression conferred marked in vitro and in vivo neuroprotection against 6-OHDA toxicity in DA neurons, and preserved motor functions involving the dopamine system in mouse. In addition to its role as an antioxidant enzyme, PRX2 exhibited anti-apoptotic effects in DA neurons via suppression of apoptosis signal-regulating kinase (ASK1)-dependent activation of the c-Jun N-terminal kinase/c-Jun and p38 pro-death pathways, which are also activated in DA neurons of postmortem PD brains. PRX2 inhibited 6-OHDA-induced ASK1 activation by modulating the redox status of the endogenous ASK1 inhibitor thioredoxin (Trx). PRX2 overexpression maintained Trx in a reduced state by inhibiting the cysteine thiol-disulfide exchange, thereby preventing its dissociation from ASK1. This study describes a previously undefined mechanism by which redox-sensitive molecules signal via apoptotic pathways in response to PD-relevant toxic stress in DA neurons. Our results also suggest that PRX2 and ASK1 may be potential targets for neuroprotective intervention in PD.
authors.affiliation: Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Weng
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Armando
authors.initials: A
authors.lastname: Signore
authors.forename: Jianhui
authors.initials: J
authors.lastname: Zhu
authors.forename: Teresa
authors.initials: T
authors.lastname: Hastings
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Greenamyre
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003580:Cytochromes / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007211:Indoles; D048848:MAP Kinase Kinase Kinase 5 / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000517:prevention & control*; D058632:Neuroprostanes / Q000627:therapeutic use*; D016627:Oxidopamine / Q000009:adverse effects; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D054464:Peroxiredoxins / Q000627:therapeutic use*; D011180:Postmortem Changes; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013879:Thioredoxins / Q000494:pharmacology
chemical_list: D003580:Cytochromes; D004791:Enzyme Inhibitors; D007211:Indoles; D058632:Neuroprostanes; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C007293:DAPI; D013879:Thioredoxins; D016627:Oxidopamine; D054464:Peroxiredoxins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D001058:Apomorphine; D004298:Dopamine