title: Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection.
abstract: Incidence of Parkinson's disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.
authors.affiliation: Division of Molecular and Cellular Neurosciences, National Brain Research Centre, Nainwal Mode, Manesar 122050, India.
authors.forename: Uzma
authors.initials: U
authors.lastname: Saeed
authors.forename: Smitha
authors.initials: S
authors.lastname: Karunakaran
authors.forename: Durga Praveen
authors.initials: DP
authors.lastname: Meka
authors.forename: Ratnacaram Chandrahaas
authors.initials: RC
authors.lastname: Koumar
authors.forename: Sujanitha
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: Shanker Datt
authors.initials: SD
authors.lastname: Joshi
authors.forename: Prakash
authors.initials: P
authors.lastname: Nidadavolu
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D056970:Co-Repressor Proteins; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005980:Glutathione Reductase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018832:Molecular Chaperones; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D021381:Protein Transport / Q000187:drug effects; D012737:Sex Factors; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009498:Neurotoxins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D009243:NAD; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D054464:Peroxiredoxins; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D004298:Dopamine