Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system
Identifieur interne : 000121 ( PascalFrancis/Checkpoint ); précédent : 000120; suivant : 000122Selective 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.
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- Wicri :
- topic : Génétique.
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- 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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<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>
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<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>
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<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>
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<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>
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<fA11 i1="01" i2="1"><s1>XILOURI (Maria)</s1>
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</fA11>
<fA11 i1="05" i2="1"><s1>PERIER (Celine)</s1>
</fA11>
<fA11 i1="06" i2="1"><s1>VILA (Miquel)</s1>
</fA11>
<fA11 i1="07" i2="1"><s1>MANIATI (Matina)</s1>
</fA11>
<fA11 i1="08" i2="1"><s1>ULUSOY (Ayse)</s1>
</fA11>
<fA11 i1="09" i2="1"><s1>KIRIK (Deniz)</s1>
</fA11>
<fA11 i1="10" i2="1"><s1>PARK (David S.)</s1>
</fA11>
<fA11 i1="11" i2="1"><s1>WADA (Keiji)</s1>
</fA11>
<fA11 i1="12" i2="1"><s1>STEFANIS (Leonidas)</s1>
</fA11>
<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>
</fA14>
<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>
</fA14>
<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>
</fA14>
<fA14 i1="04"><s1>Catalan Institution for Research and Advanced Studies (ICREA)</s1>
<s2>08010 Barcelona</s2>
<s3>ESP</s3>
<sZ>6 aut.</sZ>
</fA14>
<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>
</fA14>
<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>
</fA14>
<fA14 i1="07"><s1>Neuroscience Lab, University of Ottawa</s1>
<s2>Ottawa, ON</s2>
<s3>CAN</s3>
<sZ>10 aut.</sZ>
</fA14>
<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>
</fA14>
<fA14 i1="09"><s1>Second Department of Neurology, University of Athens Medical School</s1>
<s2>Athens</s2>
<s3>GRC</s3>
<sZ>12 aut.</sZ>
</fA14>
<fA20><s1>874-889</s1>
</fA20>
<fA21><s1>2012</s1>
</fA21>
<fA23 i1="01"><s0>ENG</s0>
</fA23>
<fA43 i1="01"><s1>INIST</s1>
<s2>22540</s2>
<s5>354000508403300130</s5>
</fA43>
<fA44><s0>0000</s0>
<s1>© 2012 INIST-CNRS. All rights reserved.</s1>
</fA44>
<fA45><s0>66 ref.</s0>
</fA45>
<fA47 i1="01" i2="1"><s0>12-0122767</s0>
</fA47>
<fA60><s1>P</s1>
</fA60>
<fA61><s0>A</s0>
</fA61>
<fA64 i1="01" i2="1"><s0>Human molecular genetics : (Print)</s0>
</fA64>
<fA66 i1="01"><s0>GBR</s0>
</fA66>
<fC01 i1="01" l="ENG"><s0>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.</s0>
</fC01>
<fC02 i1="01" i2="X"><s0>002A04</s0>
</fC02>
<fC02 i1="02" i2="X"><s0>002A07</s0>
</fC02>
<fC03 i1="01" i2="X" l="FRE"><s0>Neuroprotection</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="ENG"><s0>Neuroprotection</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="SPA"><s0>Neuroprotección</s0>
<s5>01</s5>
</fC03>
<fC03 i1="02" i2="X" l="FRE"><s0>Polymorphisme</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="ENG"><s0>Polymorphism</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="SPA"><s0>Polimorfismo</s0>
<s5>02</s5>
</fC03>
<fC03 i1="03" i2="X" l="FRE"><s0>Variant</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="ENG"><s0>Variant</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="SPA"><s0>Variante</s0>
<s5>03</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE"><s0>Variabilité génétique</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Genetic variability</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Variabilidad genética</s0>
<s5>04</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Génotype</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Genotype</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA"><s0>Genotipo</s0>
<s5>05</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE"><s0>Génétique</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG"><s0>Genetics</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Genética</s0>
<s5>06</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>Ubiquitin carboxy-terminal hydrolase L1</s0>
<s4>INC</s4>
<s5>88</s5>
</fC03>
<fN21><s1>093</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
</pA>
</standard>
</inist>
<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>
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