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In the current study, we demonstrate pAkt loss in ventral midbrain of mice treated with dopaminergic neurotoxin, 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine (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\n                    <jats:sup>+<\/jats:sup>\n                    \u2010mediated pAkt loss. We demonstrate for the first time the selective loss of Akt activity,\n                    <jats:italic>in vivo<\/jats:italic>\n                    , due to oxidative modification of Akt and provide mechanistic insight into oxidative stress\u2010induced down\u2010regulation of cell survival pathway in mouse midbrain following exposure to MPTP.\u2014Durgadoss, L., Nidadavolu, P., Khader Valli, R., Saeed, U., Mishra, M., Seth, P., Ravindranath, R. Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down\u2010regulation of pAkt.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    26, 1473\u20101483 (2012).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.11-194100","type":"journal-article","created":{"date-parts":[[2011,12,23]],"date-time":"2011-12-23T23:45:13Z","timestamp":1324683913000},"page":"1473-1483","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down\u2010regulation of pAkt"],"prefix":"10.1096","volume":"26","author":[{"given":"Lalitha","family":"Durgadoss","sequence":"first","affiliation":[{"name":"Division of Molecular and Cellular Neurosciences National Brain Research Centre Nainwal Mode Manesar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Nidadavolu","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Neurosciences National Brain Research Centre Nainwal Mode Manesar India"},{"name":"Centre for Neuroscience Indian Institute of Science Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupanagudi Khader","family":"Valli","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Neurosciences National Brain Research Centre Nainwal Mode Manesar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uzma","family":"Saeed","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Neurosciences National Brain Research Centre Nainwal Mode Manesar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamata","family":"Mishra","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Neurosciences National Brain Research Centre Nainwal Mode Manesar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Seth","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Neurosciences National Brain Research Centre Nainwal Mode Manesar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayalakshmi","family":"Ravindranath","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Neurosciences National Brain Research Centre Nainwal Mode Manesar India"},{"name":"Centre for Neuroscience Indian Institute of Science Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,12,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00831.x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2006.06.003"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2009.09.055"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3928-08.2008"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05588.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2010.07.008"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.04.085"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504610102"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20609"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.105.018671"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1159\/000091206"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M601984200"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-007-0065-9"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04149.x"},{"key":"e_1_2_7_16_1","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1523\/JNEUROSCI.3944-09.2010","article-title":"Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease","volume":"30","author":"Malagelada C.","year":"2009","journal-title":"J. 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