Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system
Identifieur interne : 001496 ( Main/Exploration ); précédent : 001495; suivant : 001497Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system
Auteurs : Maria Xilouri [Grèce] ; Elli Kyratzi [Grèce] ; Pothitos M. Pitychoutis [Grèce] ; Zoi Papadopoulou-Daifoti [Grèce] ; Celine Perier [Espagne] ; Miquel Vila [Espagne] ; Matina Maniati [Grèce] ; Ayse Ulusoy [Suède] ; Deniz Kirik [Suède] ; David S. Park [Canada] ; Keiji Wada [Japon] ; Leonidas Stefanis [Grèce]Source :
- Human molecular genetics : (Print) [ 0964-6906 ] ; 2012.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Génétique.
English descriptors
- KwdEn :
Abstract
Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1 protein (gracile axonal dystrophy mice). Our findings show that the lack of wild-type (WT) UCH-L1 does not influence to any significant degree the dopaminergic system at baseline or following injections of the neurotoxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, using a novel intrastriatal adenoviral injection protocol, we have found that mouse nigral neurons retrogradely transduced with S18Y UCH-L1, but not the WT protein, are significantly protected against MPTP toxicity. Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role.
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Park</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Neuroscience Lab, University of Ottawa</s1><s2>Ottawa, ON</s2><s3>CAN</s3><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, ON</wicri:noRegion></affiliation></author><author><name sortKey="Wada, Keiji" sort="Wada, Keiji" uniqKey="Wada K" first="Keiji" last="Wada">Keiji Wada</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry</s1><s2>Tokyo 187-8502</s2><s3>JPN</s3><sZ>11 aut.</sZ></inist:fA14><country>Japon</country><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Second Department of Neurology, University of Athens Medical School</s1><s2>Athens</s2><s3>GRC</s3><sZ>12 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">12-0122767</idno><date when="2012">2012</date><idno type="stanalyst">PASCAL 12-0122767 INIST</idno><idno type="RBID">Pascal:12-0122767</idno><idno type="wicri:Area/PascalFrancis/Corpus">000219</idno><idno type="wicri:Area/PascalFrancis/Curation">000A33</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000121</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000121</idno><idno type="wicri:doubleKey">0964-6906:2012:Xilouri M:selective:neuroprotective:effects</idno><idno type="wicri:Area/Main/Merge">001535</idno><idno type="wicri:Area/Main/Curation">001496</idno><idno type="wicri:Area/Main/Exploration">001496</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system</title><author><name sortKey="Xilouri, Maria" sort="Xilouri, Maria" uniqKey="Xilouri M" first="Maria" last="Xilouri">Maria Xilouri</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation></author><author><name sortKey="Kyratzi, Elli" sort="Kyratzi, Elli" uniqKey="Kyratzi E" first="Elli" last="Kyratzi">Elli Kyratzi</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation></author><author><name sortKey="Pitychoutis, Pothitos M" sort="Pitychoutis, Pothitos M" uniqKey="Pitychoutis P" first="Pothitos M." last="Pitychoutis">Pothitos M. Pitychoutis</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pharmacology, Medical School, University of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation></author><author><name sortKey="Papadopoulou Daifoti, Zoi" sort="Papadopoulou Daifoti, Zoi" uniqKey="Papadopoulou Daifoti Z" first="Zoi" last="Papadopoulou-Daifoti">Zoi Papadopoulou-Daifoti</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pharmacology, Medical School, University of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation></author><author><name sortKey="Perier, Celine" sort="Perier, Celine" uniqKey="Perier C" first="Celine" last="Perier">Celine Perier</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED)</s1><s2>Barcelona 08035</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED)</s1><s2>Barcelona 08035</s2><s3>ESP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Catalan Institution for Research and Advanced Studies (ICREA)</s1><s2>08010 Barcelona</s2><s3>ESP</s3><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona</s1><s2>08193 Bellaterra, Barcelona</s2><s3>ESP</s3><sZ>6 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Maniati, Matina" sort="Maniati, Matina" uniqKey="Maniati M" first="Matina" last="Maniati">Matina Maniati</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation></author><author><name sortKey="Ulusoy, Ayse" sort="Ulusoy, Ayse" uniqKey="Ulusoy A" first="Ayse" last="Ulusoy">Ayse Ulusoy</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University</s1><s2>Lund</s2><s3>SWE</s3><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Suède</country><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University</s1><s2>Lund</s2><s3>SWE</s3><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Suède</country><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Neuroscience Lab, University of Ottawa</s1><s2>Ottawa, ON</s2><s3>CAN</s3><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, ON</wicri:noRegion></affiliation></author><author><name sortKey="Wada, Keiji" sort="Wada, Keiji" uniqKey="Wada K" first="Keiji" last="Wada">Keiji Wada</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry</s1><s2>Tokyo 187-8502</s2><s3>JPN</s3><sZ>11 aut.</sZ></inist:fA14><country>Japon</country><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Second Department of Neurology, University of Athens Medical School</s1><s2>Athens</s2><s3>GRC</s3><sZ>12 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>Athens</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Human molecular genetics : (Print)</title><title level="j" type="abbreviated">Hum. mol. genet. : (Print)</title><idno type="ISSN">0964-6906</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Human molecular genetics : (Print)</title><title level="j" type="abbreviated">Hum. mol. genet. : (Print)</title><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Genetic variability</term><term>Genetics</term><term>Genotype</term><term>Neuroprotection</term><term>Polymorphism</term><term>Variant</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Neuroprotection</term><term>Polymorphisme</term><term>Variant</term><term>Variabilité génétique</term><term>Génotype</term><term>Génétique</term><term>Ubiquitin carboxy-terminal hydrolase L1</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1 protein (gracile axonal dystrophy mice). Our findings show that the lack of wild-type (WT) UCH-L1 does not influence to any significant degree the dopaminergic system at baseline or following injections of the neurotoxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, using a novel intrastriatal adenoviral injection protocol, we have found that mouse nigral neurons retrogradely transduced with S18Y UCH-L1, but not the WT protein, are significantly protected against MPTP toxicity. Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Espagne</li><li>Grèce</li><li>Japon</li><li>Suède</li></country><region><li>Catalogne</li></region><settlement><li>Barcelone</li><li>Tokyo</li></settlement></list><tree><country name="Grèce"><noRegion><name sortKey="Xilouri, Maria" sort="Xilouri, Maria" uniqKey="Xilouri M" first="Maria" last="Xilouri">Maria Xilouri</name></noRegion><name sortKey="Kyratzi, Elli" sort="Kyratzi, Elli" uniqKey="Kyratzi E" first="Elli" last="Kyratzi">Elli Kyratzi</name><name sortKey="Maniati, Matina" sort="Maniati, Matina" uniqKey="Maniati M" first="Matina" last="Maniati">Matina Maniati</name><name sortKey="Papadopoulou Daifoti, Zoi" sort="Papadopoulou Daifoti, Zoi" uniqKey="Papadopoulou Daifoti Z" first="Zoi" last="Papadopoulou-Daifoti">Zoi Papadopoulou-Daifoti</name><name sortKey="Pitychoutis, Pothitos M" sort="Pitychoutis, Pothitos M" uniqKey="Pitychoutis P" first="Pothitos M." last="Pitychoutis">Pothitos M. Pitychoutis</name><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name></country><country name="Espagne"><region name="Catalogne"><name sortKey="Perier, Celine" sort="Perier, Celine" uniqKey="Perier C" first="Celine" last="Perier">Celine Perier</name></region><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name></country><country name="Suède"><noRegion><name sortKey="Ulusoy, Ayse" sort="Ulusoy, Ayse" uniqKey="Ulusoy A" first="Ayse" last="Ulusoy">Ayse Ulusoy</name></noRegion><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name></country><country name="Canada"><noRegion><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name></noRegion></country><country name="Japon"><noRegion><name sortKey="Wada, Keiji" sort="Wada, Keiji" uniqKey="Wada K" first="Keiji" last="Wada">Keiji Wada</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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