Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease.
Identifieur interne : 002440 ( Main/Exploration ); précédent : 002439; suivant : 002441Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease.
Auteurs : Dianbo Qu [Canada] ; Juliet Rashidian ; Matthew P. Mount ; Hossein Aleyasin ; Mohammad Parsanejad ; Arman Lira ; Emdadul Haque ; Yi Zhang ; Steve Callaghan ; Mireille Daigle ; Maxime W C. Rousseaux ; Ruth S. Slack ; Paul R. Albert ; Inez Vincent ; John M. Woulfe ; David S. ParkSource :
- Neuron [ 0896-6273 ] ; 2007.
English descriptors
- KwdEn :
- Adenoviridae (genetics), Amino Acid Sequence, Animals, Blotting, Western, Cells, Cultured, Cerebral Cortex (cytology), Cerebral Cortex (enzymology), Cerebral Cortex (metabolism), Cyclin-Dependent Kinase 5 (physiology), Gene Transfer Techniques, Homeodomain Proteins (metabolism), Homeodomain Proteins (physiology), Immunohistochemistry, Immunoprecipitation, MPTP Poisoning (metabolism), Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Neurons (enzymology), Neurons (metabolism), Parkinson Disease, Secondary (chemically induced), Parkinson Disease, Secondary (metabolism), Phosphorylation, Reactive Oxygen Species (metabolism), Substantia Nigra (cytology), Substantia Nigra (enzymology).
- MESH :
- chemical , metabolism : Homeodomain Proteins, Reactive Oxygen Species.
- chemical , physiology : Cyclin-Dependent Kinase 5, Homeodomain Proteins.
- chemically induced : Parkinson Disease, Secondary.
- cytology : Cerebral Cortex, Substantia Nigra.
- enzymology : Cerebral Cortex, Neurons, Substantia Nigra.
- genetics : Adenoviridae.
- metabolism : Cerebral Cortex, MPTP Poisoning, Neurons, Parkinson Disease, Secondary.
- Amino Acid Sequence, Animals, Blotting, Western, Cells, Cultured, Gene Transfer Techniques, Immunohistochemistry, Immunoprecipitation, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Phosphorylation.
Abstract
We reported previously that calpain-mediated Cdk5 activation is critical for mitochondrial toxin-induced dopaminergic death. Here, we report a target that mediates this loss. Prx2, an antioxidant enzyme, binds Cdk5/p35. Prx2 is phosphorylated at T89 in neurons treated with MPP+ and/or MPTP in animals in a calpain/Cdk5/p35-dependent manner. This phosphorylation reduces Prx2 peroxidase activity. Consistent with this, p35-/- neurons show reduced oxidative stress upon MPP+ treatment. Expression of Prx2 and Prx2T89A, but not the phosphorylation mimic Prx2T89E, protects cultured and adult neurons following mitochondrial insult. Finally, downregulation of Prx2 increases oxidative stress and sensitivity to MPP+. We propose a mechanistic model by which mitochondrial toxin leads to calpain-mediated Cdk5 activation, reduced Prx2 activity, and decreased capacity to eliminate ROS. Importantly, increased Prx2 phosphorylation also occurs in nigral neurons from postmortem tissue from Parkinson's disease patients when compared to control, suggesting the relevance of this pathway in the human condition.
DOI: 10.1016/j.neuron.2007.05.033
PubMed: 17610816
Affiliations:
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Mount</name></author><author><name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name></author><author><name sortKey="Parsanejad, Mohammad" sort="Parsanejad, Mohammad" uniqKey="Parsanejad M" first="Mohammad" last="Parsanejad">Mohammad Parsanejad</name></author><author><name sortKey="Lira, Arman" sort="Lira, Arman" uniqKey="Lira A" first="Arman" last="Lira">Arman Lira</name></author><author><name sortKey="Haque, Emdadul" sort="Haque, Emdadul" uniqKey="Haque E" first="Emdadul" last="Haque">Emdadul Haque</name></author><author><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name></author><author><name sortKey="Callaghan, Steve" sort="Callaghan, Steve" uniqKey="Callaghan S" first="Steve" last="Callaghan">Steve Callaghan</name></author><author><name sortKey="Daigle, Mireille" sort="Daigle, Mireille" uniqKey="Daigle M" first="Mireille" last="Daigle">Mireille Daigle</name></author><author><name sortKey="Rousseaux, Maxime W C" sort="Rousseaux, Maxime W C" uniqKey="Rousseaux M" first="Maxime W C" last="Rousseaux">Maxime W C. 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Mount</name></author><author><name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name></author><author><name sortKey="Parsanejad, Mohammad" sort="Parsanejad, Mohammad" uniqKey="Parsanejad M" first="Mohammad" last="Parsanejad">Mohammad Parsanejad</name></author><author><name sortKey="Lira, Arman" sort="Lira, Arman" uniqKey="Lira A" first="Arman" last="Lira">Arman Lira</name></author><author><name sortKey="Haque, Emdadul" sort="Haque, Emdadul" uniqKey="Haque E" first="Emdadul" last="Haque">Emdadul Haque</name></author><author><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name></author><author><name sortKey="Callaghan, Steve" sort="Callaghan, Steve" uniqKey="Callaghan S" first="Steve" last="Callaghan">Steve Callaghan</name></author><author><name sortKey="Daigle, Mireille" sort="Daigle, Mireille" uniqKey="Daigle M" first="Mireille" last="Daigle">Mireille Daigle</name></author><author><name sortKey="Rousseaux, Maxime W C" sort="Rousseaux, Maxime W C" uniqKey="Rousseaux M" first="Maxime W C" last="Rousseaux">Maxime W C. Rousseaux</name></author><author><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S" last="Slack">Ruth S. Slack</name></author><author><name sortKey="Albert, Paul R" sort="Albert, Paul R" uniqKey="Albert P" first="Paul R" last="Albert">Paul R. Albert</name></author><author><name sortKey="Vincent, Inez" sort="Vincent, Inez" uniqKey="Vincent I" first="Inez" last="Vincent">Inez Vincent</name></author><author><name sortKey="Woulfe, John M" sort="Woulfe, John M" uniqKey="Woulfe J" first="John M" last="Woulfe">John M. Woulfe</name></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name></author></analytic><series><title level="j">Neuron</title><idno type="ISSN">0896-6273</idno><imprint><date when="2007" type="published">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenoviridae (genetics)</term><term>Amino Acid Sequence</term><term>Animals</term><term>Blotting, Western</term><term>Cells, Cultured</term><term>Cerebral Cortex (cytology)</term><term>Cerebral Cortex (enzymology)</term><term>Cerebral Cortex (metabolism)</term><term>Cyclin-Dependent Kinase 5 (physiology)</term><term>Gene Transfer Techniques</term><term>Homeodomain Proteins (metabolism)</term><term>Homeodomain Proteins (physiology)</term><term>Immunohistochemistry</term><term>Immunoprecipitation</term><term>MPTP Poisoning (metabolism)</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Molecular Sequence Data</term><term>Neurons (enzymology)</term><term>Neurons (metabolism)</term><term>Parkinson Disease, Secondary (chemically induced)</term><term>Parkinson Disease, Secondary (metabolism)</term><term>Phosphorylation</term><term>Reactive Oxygen Species (metabolism)</term><term>Substantia Nigra (cytology)</term><term>Substantia Nigra (enzymology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Homeodomain Proteins</term><term>Reactive Oxygen Species</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Cyclin-Dependent Kinase 5</term><term>Homeodomain Proteins</term></keywords><keywords scheme="MESH" qualifier="chemically induced" xml:lang="en"><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Cerebral Cortex</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Cerebral Cortex</term><term>Neurons</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Adenoviridae</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cerebral Cortex</term><term>MPTP Poisoning</term><term>Neurons</term><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Blotting, Western</term><term>Cells, Cultured</term><term>Gene Transfer Techniques</term><term>Immunohistochemistry</term><term>Immunoprecipitation</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Molecular Sequence Data</term><term>Phosphorylation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We reported previously that calpain-mediated Cdk5 activation is critical for mitochondrial toxin-induced dopaminergic death. Here, we report a target that mediates this loss. Prx2, an antioxidant enzyme, binds Cdk5/p35. Prx2 is phosphorylated at T89 in neurons treated with MPP+ and/or MPTP in animals in a calpain/Cdk5/p35-dependent manner. This phosphorylation reduces Prx2 peroxidase activity. Consistent with this, p35-/- neurons show reduced oxidative stress upon MPP+ treatment. Expression of Prx2 and Prx2T89A, but not the phosphorylation mimic Prx2T89E, protects cultured and adult neurons following mitochondrial insult. Finally, downregulation of Prx2 increases oxidative stress and sensitivity to MPP+. We propose a mechanistic model by which mitochondrial toxin leads to calpain-mediated Cdk5 activation, reduced Prx2 activity, and decreased capacity to eliminate ROS. Importantly, increased Prx2 phosphorylation also occurs in nigral neurons from postmortem tissue from Parkinson's disease patients when compared to control, suggesting the relevance of this pathway in the human condition.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Albert, Paul R" sort="Albert, Paul R" uniqKey="Albert P" first="Paul R" last="Albert">Paul R. Albert</name><name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name><name sortKey="Callaghan, Steve" sort="Callaghan, Steve" uniqKey="Callaghan S" first="Steve" last="Callaghan">Steve Callaghan</name><name sortKey="Daigle, Mireille" sort="Daigle, Mireille" uniqKey="Daigle M" first="Mireille" last="Daigle">Mireille Daigle</name><name sortKey="Haque, Emdadul" sort="Haque, Emdadul" uniqKey="Haque E" first="Emdadul" last="Haque">Emdadul Haque</name><name sortKey="Lira, Arman" sort="Lira, Arman" uniqKey="Lira A" first="Arman" last="Lira">Arman Lira</name><name sortKey="Mount, Matthew P" sort="Mount, Matthew P" uniqKey="Mount M" first="Matthew P" last="Mount">Matthew P. Mount</name><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name><name sortKey="Parsanejad, Mohammad" sort="Parsanejad, Mohammad" uniqKey="Parsanejad M" first="Mohammad" last="Parsanejad">Mohammad Parsanejad</name><name sortKey="Rashidian, Juliet" sort="Rashidian, Juliet" uniqKey="Rashidian J" first="Juliet" last="Rashidian">Juliet Rashidian</name><name sortKey="Rousseaux, Maxime W C" sort="Rousseaux, Maxime W C" uniqKey="Rousseaux M" first="Maxime W C" last="Rousseaux">Maxime W C. Rousseaux</name><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S" last="Slack">Ruth S. Slack</name><name sortKey="Vincent, Inez" sort="Vincent, Inez" uniqKey="Vincent I" first="Inez" last="Vincent">Inez Vincent</name><name sortKey="Woulfe, John M" sort="Woulfe, John M" uniqKey="Woulfe J" first="John M" last="Woulfe">John M. Woulfe</name><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name></noCountry><country name="Canada"><noRegion><name sortKey="Qu, Dianbo" sort="Qu, Dianbo" uniqKey="Qu D" first="Dianbo" last="Qu">Dianbo Qu</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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