Mixed lineage kinase-c-jun N-terminal kinase signaling pathway : A new therapeutic target in Parkinson's disease
Identifieur interne : 001D94 ( PascalFrancis/Checkpoint ); précédent : 001D93; suivant : 001D95Mixed lineage kinase-c-jun N-terminal kinase signaling pathway : A new therapeutic target in Parkinson's disease
Auteurs : Robert M. Silva [États-Unis] ; Chia-Yi Kuan [États-Unis] ; Pasko Rakic [États-Unis] ; Robert E. Burke [États-Unis]Source :
- Movement disorders [ 0885-3185 ] ; 2005.
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- Pascal (Inist)
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Abstract
There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) -c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway.
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Silva</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Neurology, The College of Physicians and Surgeons, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation></author><author><name sortKey="Kuan, Chia Yi" sort="Kuan, Chia Yi" uniqKey="Kuan C" first="Chia-Yi" last="Kuan">Chia-Yi Kuan</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation</s1><s2>Cincinnati Ohio</s2><s3>USA</s3><sZ>2 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Cincinnati Ohio</wicri:noRegion></affiliation></author><author><name sortKey="Rakic, Pasko" sort="Rakic, Pasko" uniqKey="Rakic P" first="Pasko" last="Rakic">Pasko Rakic</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Neurobiology, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Burke, Robert E" sort="Burke, Robert E" uniqKey="Burke R" first="Robert E." last="Burke">Robert E. 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Silva</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Neurology, The College of Physicians and Surgeons, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation></author><author><name sortKey="Kuan, Chia Yi" sort="Kuan, Chia Yi" uniqKey="Kuan C" first="Chia-Yi" last="Kuan">Chia-Yi Kuan</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation</s1><s2>Cincinnati Ohio</s2><s3>USA</s3><sZ>2 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Cincinnati Ohio</wicri:noRegion></affiliation></author><author><name sortKey="Rakic, Pasko" sort="Rakic, Pasko" uniqKey="Rakic P" first="Pasko" last="Rakic">Pasko Rakic</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Neurobiology, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Burke, Robert E" sort="Burke, Robert E" uniqKey="Burke R" first="Robert E." last="Burke">Robert E. Burke</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Neurology, The College of Physicians and Surgeons, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Department of Pathology, The College of Physicians and Surgeons, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation></author></analytic><series><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apoptosis</term><term>C-Onc gene</term><term>Cell death</term><term>Kinase</term><term>Nervous system diseases</term><term>Parkinson disease</term><term>Signal transduction</term><term>Treatment</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Système nerveux pathologie</term><term>Parkinson maladie</term><term>Kinase</term><term>Gène onc cellulaire</term><term>Transduction signal</term><term>Traitement</term><term>Apoptose</term><term>Mort cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) -c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0885-3185</s0></fA01><fA03 i2="1"><s0>Mov. disord.</s0></fA03><fA05><s2>20</s2></fA05><fA06><s2>6</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Mixed lineage kinase-c-jun N-terminal kinase signaling pathway : A new therapeutic target in Parkinson's disease</s1></fA08><fA11 i1="01" i2="1"><s1>SILVA (Robert M.)</s1></fA11><fA11 i1="02" i2="1"><s1>KUAN (Chia-Yi)</s1></fA11><fA11 i1="03" i2="1"><s1>RAKIC (Pasko)</s1></fA11><fA11 i1="04" i2="1"><s1>BURKE (Robert E.)</s1></fA11><fA14 i1="01"><s1>Department of Neurology, The College of Physicians and Surgeons, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></fA14><fA14 i1="02"><s1>Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation</s1><s2>Cincinnati Ohio</s2><s3>USA</s3><sZ>2 aut.</sZ></fA14><fA14 i1="03"><s1>Department of Neurobiology, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ></fA14><fA14 i1="04"><s1>Department of Pathology, The College of Physicians and Surgeons, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>4 aut.</sZ></fA14><fA20><s1>653-664</s1></fA20><fA21><s1>2005</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>20953</s2><s5>354000138604660010</s5></fA43><fA44><s0>0000</s0><s1>© 2005 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>112 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>05-0363473</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Movement disorders</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) -c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. 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Silva</name></region><name sortKey="Burke, Robert E" sort="Burke, Robert E" uniqKey="Burke R" first="Robert E." last="Burke">Robert E. Burke</name><name sortKey="Burke, Robert E" sort="Burke, Robert E" uniqKey="Burke R" first="Robert E." last="Burke">Robert E. Burke</name><name sortKey="Kuan, Chia Yi" sort="Kuan, Chia Yi" uniqKey="Kuan C" first="Chia-Yi" last="Kuan">Chia-Yi Kuan</name><name sortKey="Rakic, Pasko" sort="Rakic, Pasko" uniqKey="Rakic P" first="Pasko" last="Rakic">Pasko Rakic</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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