Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system.
Identifieur interne : 001133 ( Main/Exploration ); précédent : 001132; suivant : 001134Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system.
Auteurs : Maria Xilouri [Grèce] ; Elli Kyratzi ; Pothitos M. Pitychoutis ; Zoi Papadopoulou-Daifoti ; Celine Perier ; Miquel Vila ; Matina Maniati ; Ayse Ulusoy ; Deniz Kirik ; David S. Park ; Keiji Wada ; Leonidas StefanisSource :
- Human molecular genetics [ 1460-2083 ] ; 2012.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology), Adenoviridae (genetics), Animals, Antioxidants (metabolism), Cell Death (drug effects), Dopamine (metabolism), Dopaminergic Neurons (drug effects), Dopaminergic Neurons (metabolism), Dopaminergic Neurons (pathology), Genetic Vectors (genetics), Humans, MPTP Poisoning (pathology), MPTP Poisoning (prevention & control), Male, Mice, Mice, Inbred C57BL, Neostriatum (cytology), Neostriatum (metabolism), Neuroprotective Agents, Oxidative Stress (drug effects), Parkinson Disease (metabolism), Polymorphism, Genetic (genetics), Ubiquitin Thiolesterase (deficiency), Ubiquitin Thiolesterase (genetics), Ubiquitin Thiolesterase (metabolism).
- MESH :
- chemical , deficiency : Ubiquitin Thiolesterase.
- chemical , genetics : Ubiquitin Thiolesterase.
- chemical , metabolism : Antioxidants, Dopamine, Ubiquitin Thiolesterase.
- chemical , pharmacology : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
- cytology : Neostriatum.
- drug effects : Cell Death, Dopaminergic Neurons, Oxidative Stress.
- genetics : Adenoviridae, Genetic Vectors, Polymorphism, Genetic.
- metabolism : Dopaminergic Neurons, Neostriatum, Parkinson Disease.
- pathology : Dopaminergic Neurons, MPTP Poisoning.
- prevention & control : MPTP Poisoning.
- Animals, Humans, Male, Mice, Mice, Inbred C57BL, Neuroprotective Agents.
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.
DOI: 10.1093/hmg/ddr521
PubMed: 22076440
Affiliations:
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Park</name></author><author><name sortKey="Wada, Keiji" sort="Wada, Keiji" uniqKey="Wada K" first="Keiji" last="Wada">Keiji Wada</name></author><author><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2012">2012</date><idno type="RBID">pubmed:22076440</idno><idno type="pmid">22076440</idno><idno type="doi">10.1093/hmg/ddr521</idno><idno type="wicri:Area/PubMed/Corpus">000B00</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000B00</idno><idno type="wicri:Area/PubMed/Curation">000B00</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000B00</idno><idno type="wicri:Area/PubMed/Checkpoint">000B00</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000B00</idno><idno type="wicri:Area/Ncbi/Merge">001002</idno><idno type="wicri:Area/Ncbi/Curation">001002</idno><idno type="wicri:Area/Ncbi/Checkpoint">001002</idno><idno type="wicri:Area/Main/Merge">001154</idno><idno type="wicri:Area/Main/Curation">001133</idno><idno type="wicri:Area/Main/Exploration">001133</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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"><nlm:affiliation>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. mxilouri@bioacademy.gr</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens</wicri:regionArea><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></author><author><name sortKey="Pitychoutis, Pothitos M" sort="Pitychoutis, Pothitos M" uniqKey="Pitychoutis P" first="Pothitos M" last="Pitychoutis">Pothitos M. Pitychoutis</name></author><author><name sortKey="Papadopoulou Daifoti, Zoi" sort="Papadopoulou Daifoti, Zoi" uniqKey="Papadopoulou Daifoti Z" first="Zoi" last="Papadopoulou-Daifoti">Zoi Papadopoulou-Daifoti</name></author><author><name sortKey="Perier, Celine" sort="Perier, Celine" uniqKey="Perier C" first="Celine" last="Perier">Celine Perier</name></author><author><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name></author><author><name sortKey="Maniati, Matina" sort="Maniati, Matina" uniqKey="Maniati M" first="Matina" last="Maniati">Matina Maniati</name></author><author><name sortKey="Ulusoy, Ayse" sort="Ulusoy, Ayse" uniqKey="Ulusoy A" first="Ayse" last="Ulusoy">Ayse Ulusoy</name></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</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><author><name sortKey="Wada, Keiji" sort="Wada, Keiji" uniqKey="Wada K" first="Keiji" last="Wada">Keiji Wada</name></author><author><name sortKey="Stefanis, Leonidas" sort="Stefanis, Leonidas" uniqKey="Stefanis L" first="Leonidas" last="Stefanis">Leonidas Stefanis</name></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)</term><term>Adenoviridae (genetics)</term><term>Animals</term><term>Antioxidants (metabolism)</term><term>Cell Death (drug effects)</term><term>Dopamine (metabolism)</term><term>Dopaminergic Neurons (drug effects)</term><term>Dopaminergic Neurons (metabolism)</term><term>Dopaminergic Neurons (pathology)</term><term>Genetic Vectors (genetics)</term><term>Humans</term><term>MPTP Poisoning (pathology)</term><term>MPTP Poisoning (prevention & control)</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Neostriatum (cytology)</term><term>Neostriatum (metabolism)</term><term>Neuroprotective Agents</term><term>Oxidative Stress (drug effects)</term><term>Parkinson Disease (metabolism)</term><term>Polymorphism, Genetic (genetics)</term><term>Ubiquitin Thiolesterase (deficiency)</term><term>Ubiquitin Thiolesterase (genetics)</term><term>Ubiquitin Thiolesterase (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Ubiquitin Thiolesterase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Ubiquitin Thiolesterase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antioxidants</term><term>Dopamine</term><term>Ubiquitin Thiolesterase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Neostriatum</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Death</term><term>Dopaminergic Neurons</term><term>Oxidative Stress</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Adenoviridae</term><term>Genetic Vectors</term><term>Polymorphism, Genetic</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Dopaminergic Neurons</term><term>Neostriatum</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Dopaminergic Neurons</term><term>MPTP Poisoning</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>MPTP Poisoning</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Neuroprotective Agents</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>Grèce</li></country></list><tree><noCountry><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><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="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name><name sortKey="Perier, Celine" sort="Perier, Celine" uniqKey="Perier C" first="Celine" last="Perier">Celine Perier</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="Ulusoy, Ayse" sort="Ulusoy, Ayse" uniqKey="Ulusoy A" first="Ayse" last="Ulusoy">Ayse Ulusoy</name><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><name sortKey="Wada, Keiji" sort="Wada, Keiji" uniqKey="Wada K" first="Keiji" last="Wada">Keiji Wada</name></noCountry><country name="Grèce"><noRegion><name sortKey="Xilouri, Maria" sort="Xilouri, Maria" uniqKey="Xilouri M" first="Maria" last="Xilouri">Maria Xilouri</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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