Durgadoss, Lalitha and Nidadavolu, Prakash and Valli, Rupanagudi K and Saeed, Uzma and Mishra, Mamata and Seth, Pankaj and Ravindranath, Vijayalakshmi (2012) Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt. FASEB J., 26 (4). pp. 1473-1483.

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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.

Item Type:	Article
Subjects:	Neurodegenerative Disorders Neuro-Oncological Disorders Neurocognitive Processes Neuronal Development and Regeneration Informatics and Imaging Genetics and Molecular Biology
Depositing User:	Dr. D.D. Lal
Date Deposited:	04 May 2017 06:22
Last Modified:	21 Feb 2022 06:38
URI:	http://nbrc.sciencecentral.in/id/eprint/43

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