title: Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt.
abstract: Impairment of Akt phosphorylation, a critical survival signal, has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. However, the mechanism underlying pAkt loss is unclear. In the current study, we demonstrate pAkt loss in ventral midbrain of mice treated with dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when compared to ventral midbrain of control mice treated with vehicle alone. Thiol residues of the critical cysteines in Akt are oxidized to a greater degree in mice treated with MPTP, which is reflected as a 40% loss of reduced Akt. Association of oxidatively modified Akt with the phosphatase PP2A, which can lead to enhanced dephosphorylation of pAkt, was significantly stronger after MPTP treatment. Maintaining the protein thiol homeostasis by thiol antioxidants prevented loss of reduced Akt, decreased association with PP2A, and maintained pAkt levels. Overexpression of glutaredoxin, a protein disulfide oxidoreductase, in human primary neurons helped sustain reduced state of Akt and abolished MPP(+)-mediated pAkt loss. We demonstrate for the first time the selective loss of Akt activity, in vivo, due to oxidative modification of Akt and provide mechanistic insight into oxidative stress-induced down-regulation of cell survival pathway in mouse midbrain following exposure to MPTP.
authors.affiliation: Division of Molecular and Cellular Neurosciences, National Brain Research Centre, Nainwal Mode, Manesar, India.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Durgadoss
authors.forename: Prakash
authors.initials: P
authors.lastname: Nidadavolu
authors.forename: Rupanagudi Khader
authors.initials: RK
authors.lastname: Valli
authors.forename: Uzma
authors.initials: U
authors.lastname: Saeed
authors.forename: Mamata
authors.initials: M
authors.lastname: Mishra
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D020267:MPTP Poisoning / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism
chemical_list: D000975:Antioxidants; D006540:Herbicides; D013438:Sulfhydryl Compounds; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine