Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein
Identifieur interne : 002D34 ( Main/Corpus ); précédent : 002D33; suivant : 002D35Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein
Auteurs : Masaki Wakamatsu ; Aiko Ishii ; Yuriko Ukai ; Junko Sakagami ; Shingo Iwata ; Mieko Ono ; Kayo Matsumoto ; Atsushi Nakamura ; Norihiro Tada ; Kazuto Kobayashi ; Takeshi Iwatsubo ; Makoto YoshimotoSource :
- Journal of Neuroscience Research [ 0360-4012 ] ; 2007-06.
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Abstract
Parkinson's disease is neuropathologically characterized by the presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice that expressed human α‐synuclein carrying an Ala53Thr point mutation (hα‐syn140m) under the control of the rat tyrosine hydroxylase promoter and found that hα‐syn140m was localized not only in the cytoplasm but also in the nuclei of mesencephalic dopaminergic neurons. In the present study, we carried out immunohistochemical analysis of the brain of Tg mice using anti‐PSer129, an antibody that specifically recognizes α‐synuclein phosphorylated at Ser129. The antibody detected only phosphorylated hα‐syn140m, whereas phosphorylation of endogenous α‐synuclein, if any, was below the detection limit of the method employed. The analysis showed that approximately one‐third of the hα‐syn140m‐positive neurons in the midbrain of heterozygous Tg mice were concomitantly reactive to anti‐PSer129. The ratio almost doubled in homozygotes, indicating that the phosphorylation level depends directly on the amount of substrate. In addition, the ratio did not change at least up to 48 weeks of age. These data strongly suggest that hα‐syn140m underwent constitutive phosphorylation and that the phosphorylation level was maintained to a certain level until the aged stages. Remarkably, hα‐syn140m localized in the nuclei seemed to be preferentially phosphorylated compared with that in the cytoplasm. Among kinases that have been reported to be involved in the phosphorylation of α‐synuclein, the β subunit of casein kinase‐2 was detected in the nuclei by immunohistochemistry. These data imply that at least casein kinase‐2 is involved in the phosphorylation of hα‐syn140m in the Tg mice. © 2007 Wiley‐Liss, Inc.
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DOI: 10.1002/jnr.21310
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Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Sakagami, Junko" sort="Sakagami, Junko" uniqKey="Sakagami J" first="Junko" last="Sakagami">Junko Sakagami</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Iwata, Shingo" sort="Iwata, Shingo" uniqKey="Iwata S" first="Shingo" last="Iwata">Shingo Iwata</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Ono, Mieko" sort="Ono, Mieko" uniqKey="Ono M" first="Mieko" last="Ono">Mieko Ono</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Matsumoto, Kayo" sort="Matsumoto, Kayo" uniqKey="Matsumoto K" first="Kayo" 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Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Ukai, Yuriko" sort="Ukai, Yuriko" uniqKey="Ukai Y" first="Yuriko" last="Ukai">Yuriko Ukai</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Sakagami, Junko" sort="Sakagami, Junko" uniqKey="Sakagami J" first="Junko" last="Sakagami">Junko Sakagami</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Iwata, Shingo" sort="Iwata, Shingo" uniqKey="Iwata S" first="Shingo" last="Iwata">Shingo Iwata</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Ono, Mieko" sort="Ono, Mieko" uniqKey="Ono M" first="Mieko" last="Ono">Mieko Ono</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Matsumoto, Kayo" sort="Matsumoto, Kayo" uniqKey="Matsumoto K" first="Kayo" last="Matsumoto">Kayo Matsumoto</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Nakamura, Atsushi" sort="Nakamura, Atsushi" uniqKey="Nakamura A" first="Atsushi" last="Nakamura">Atsushi Nakamura</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author><author><name sortKey="Tada, Norihiro" sort="Tada, Norihiro" uniqKey="Tada N" first="Norihiro" last="Tada">Norihiro Tada</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation><affiliation><mods:affiliation>Current Address: Atopy Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113‐8421, Japan</mods:affiliation></affiliation></author><author><name sortKey="Kobayashi, Kazuto" sort="Kobayashi, Kazuto" uniqKey="Kobayashi K" first="Kazuto" last="Kobayashi">Kazuto Kobayashi</name><affiliation><mods:affiliation>Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan</mods:affiliation></affiliation></author><author><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name><affiliation><mods:affiliation>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan</mods:affiliation></affiliation></author><author><name sortKey="Yoshimoto, Makoto" sort="Yoshimoto, Makoto" uniqKey="Yoshimoto M" first="Makoto" last="Yoshimoto">Makoto Yoshimoto</name><affiliation><mods:affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Neuroscience Research</title><title level="j" type="abbrev">J. Neurosci. Res.</title><idno type="ISSN">0360-4012</idno><idno type="eISSN">1097-4547</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2007-06">2007-06</date><biblScope unit="volume">85</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1819">1819</biblScope><biblScope unit="page" to="1825">1825</biblScope></imprint><idno type="ISSN">0360-4012</idno></series><idno type="istex">55D6D880668A55AC824B971B68CB3696639CC8B6</idno><idno type="DOI">10.1002/jnr.21310</idno><idno type="ArticleID">JNR21310</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0360-4012</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>casein kinase</term><term>dopaminergic neuron</term><term>phosphorylation</term><term>transgenic mouse</term><term>tyrosine hydroxylase</term><term>α‐synuclein</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's disease is neuropathologically characterized by the presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice that expressed human α‐synuclein carrying an Ala53Thr point mutation (hα‐syn140m) under the control of the rat tyrosine hydroxylase promoter and found that hα‐syn140m was localized not only in the cytoplasm but also in the nuclei of mesencephalic dopaminergic neurons. In the present study, we carried out immunohistochemical analysis of the brain of Tg mice using anti‐PSer129, an antibody that specifically recognizes α‐synuclein phosphorylated at Ser129. The antibody detected only phosphorylated hα‐syn140m, whereas phosphorylation of endogenous α‐synuclein, if any, was below the detection limit of the method employed. The analysis showed that approximately one‐third of the hα‐syn140m‐positive neurons in the midbrain of heterozygous Tg mice were concomitantly reactive to anti‐PSer129. The ratio almost doubled in homozygotes, indicating that the phosphorylation level depends directly on the amount of substrate. In addition, the ratio did not change at least up to 48 weeks of age. These data strongly suggest that hα‐syn140m underwent constitutive phosphorylation and that the phosphorylation level was maintained to a certain level until the aged stages. Remarkably, hα‐syn140m localized in the nuclei seemed to be preferentially phosphorylated compared with that in the cytoplasm. Among kinases that have been reported to be involved in the phosphorylation of α‐synuclein, the β subunit of casein kinase‐2 was detected in the nuclei by immunohistochemistry. These data imply that at least casein kinase‐2 is involved in the phosphorylation of hα‐syn140m in the Tg mice. © 2007 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Masaki Wakamatsu</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Aiko Ishii</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Yuriko Ukai</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Junko Sakagami</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Shingo Iwata</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Mieko Ono</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Kayo Matsumoto</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Atsushi Nakamura</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Norihiro Tada</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string><json:string>Current Address: Atopy Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113‐8421, Japan</json:string></affiliations></json:item><json:item><name>Kazuto Kobayashi</name><affiliations><json:string>Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan</json:string></affiliations></json:item><json:item><name>Takeshi Iwatsubo</name><affiliations><json:string>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan</json:string></affiliations></json:item><json:item><name>Makoto Yoshimoto</name><affiliations><json:string>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>α‐synuclein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>transgenic mouse</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>tyrosine hydroxylase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>phosphorylation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopaminergic neuron</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>casein kinase</value></json:item></subject><articleId><json:string>JNR21310</json:string></articleId><language><json:string>eng</json:string></language><abstract>Parkinson's disease is neuropathologically characterized by the presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice that expressed human α‐synuclein carrying an Ala53Thr point mutation (hα‐syn140m) under the control of the rat tyrosine hydroxylase promoter and found that hα‐syn140m was localized not only in the cytoplasm but also in the nuclei of mesencephalic dopaminergic neurons. In the present study, we carried out immunohistochemical analysis of the brain of Tg mice using anti‐PSer129, an antibody that specifically recognizes α‐synuclein phosphorylated at Ser129. The antibody detected only phosphorylated hα‐syn140m, whereas phosphorylation of endogenous α‐synuclein, if any, was below the detection limit of the method employed. The analysis showed that approximately one‐third of the hα‐syn140m‐positive neurons in the midbrain of heterozygous Tg mice were concomitantly reactive to anti‐PSer129. The ratio almost doubled in homozygotes, indicating that the phosphorylation level depends directly on the amount of substrate. In addition, the ratio did not change at least up to 48 weeks of age. These data strongly suggest that hα‐syn140m underwent constitutive phosphorylation and that the phosphorylation level was maintained to a certain level until the aged stages. Remarkably, hα‐syn140m localized in the nuclei seemed to be preferentially phosphorylated compared with that in the cytoplasm. Among kinases that have been reported to be involved in the phosphorylation of α‐synuclein, the β subunit of casein kinase‐2 was detected in the nuclei by immunohistochemistry. These data imply that at least casein kinase‐2 is involved in the phosphorylation of hα‐syn140m in the Tg mice. © 2007 Wiley‐Liss, Inc.</abstract><qualityIndicators><score>6.659</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>1777</abstractCharCount><pdfWordCount>3659</pdfWordCount><pdfCharCount>23382</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>255</abstractWordCount></qualityIndicators><title>Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein</title><genre><json:string>article</json:string></genre><host><volume>85</volume><publisherId><json:string>JNR</json:string></publisherId><pages><total>7</total><last>1825</last><first>1819</first></pages><issn><json:string>0360-4012</json:string></issn><issue>8</issue><subject><json:item><value>Research 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uri="https://api.istex.fr/document/55D6D880668A55AC824B971B68CB3696639CC8B6/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2007</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein</title><author><persName><forename type="first">Masaki</forename><surname>Wakamatsu</surname></persName><note type="biography">The first two authors contributed equally to this work.</note><affiliation>The first two authors contributed equally to this work.</affiliation><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Aiko</forename><surname>Ishii</surname></persName><note type="biography">The first two authors contributed equally to this work.</note><affiliation>The first two authors contributed equally to this work.</affiliation><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Yuriko</forename><surname>Ukai</surname></persName><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Junko</forename><surname>Sakagami</surname></persName><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Shingo</forename><surname>Iwata</surname></persName><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Mieko</forename><surname>Ono</surname></persName><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Kayo</forename><surname>Matsumoto</surname></persName><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Atsushi</forename><surname>Nakamura</surname></persName><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author><author><persName><forename type="first">Norihiro</forename><surname>Tada</surname></persName><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><affiliation>Current Address: Atopy Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113‐8421, Japan</affiliation></author><author><persName><forename type="first">Kazuto</forename><surname>Kobayashi</surname></persName><affiliation>Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan</affiliation></author><author><persName><forename type="first">Takeshi</forename><surname>Iwatsubo</surname></persName><affiliation>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan</affiliation></author><author><persName><forename type="first">Makoto</forename><surname>Yoshimoto</surname></persName><note type="correspondence"><p>Correspondence: Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Yoshino‐cho 1‐403, Kita‐ku, Saitama‐shi, Saitama 331‐9530, Japan</p></note><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation></author></analytic><monogr><title level="j">Journal of Neuroscience Research</title><title level="j" type="abbrev">J. Neurosci. Res.</title><idno type="pISSN">0360-4012</idno><idno type="eISSN">1097-4547</idno><idno type="DOI">10.1002/(ISSN)1097-4547</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2007-06"></date><biblScope unit="volume">85</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1819">1819</biblScope><biblScope unit="page" to="1825">1825</biblScope></imprint></monogr><idno type="istex">55D6D880668A55AC824B971B68CB3696639CC8B6</idno><idno type="DOI">10.1002/jnr.21310</idno><idno type="ArticleID">JNR21310</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2007</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Parkinson's disease is neuropathologically characterized by the presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice that expressed human α‐synuclein carrying an Ala53Thr point mutation (hα‐syn140m) under the control of the rat tyrosine hydroxylase promoter and found that hα‐syn140m was localized not only in the cytoplasm but also in the nuclei of mesencephalic dopaminergic neurons. In the present study, we carried out immunohistochemical analysis of the brain of Tg mice using anti‐PSer129, an antibody that specifically recognizes α‐synuclein phosphorylated at Ser129. The antibody detected only phosphorylated hα‐syn140m, whereas phosphorylation of endogenous α‐synuclein, if any, was below the detection limit of the method employed. The analysis showed that approximately one‐third of the hα‐syn140m‐positive neurons in the midbrain of heterozygous Tg mice were concomitantly reactive to anti‐PSer129. The ratio almost doubled in homozygotes, indicating that the phosphorylation level depends directly on the amount of substrate. In addition, the ratio did not change at least up to 48 weeks of age. These data strongly suggest that hα‐syn140m underwent constitutive phosphorylation and that the phosphorylation level was maintained to a certain level until the aged stages. Remarkably, hα‐syn140m localized in the nuclei seemed to be preferentially phosphorylated compared with that in the cytoplasm. Among kinases that have been reported to be involved in the phosphorylation of α‐synuclein, the β subunit of casein kinase‐2 was detected in the nuclei by immunohistochemistry. These data imply that at least casein kinase‐2 is involved in the phosphorylation of hα‐syn140m in the Tg mice. © 2007 Wiley‐Liss, Inc.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>α‐synuclein</term></item><item><term>transgenic mouse</term></item><item><term>tyrosine hydroxylase</term></item><item><term>phosphorylation</term></item><item><term>dopaminergic neuron</term></item><item><term>casein kinase</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2006-11-26">Received</change><change when="2007-02-05">Registration</change><change when="2007-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/55D6D880668A55AC824B971B68CB3696639CC8B6/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1097-4547</doi><issn type="print">0360-4012</issn><issn type="electronic">1097-4547</issn><idGroup><id type="product" value="JNR"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="JOURNAL OF NEUROSCIENCE RESEARCH">Journal of Neuroscience Research</title><title type="short">J. Neurosci. Res.</title></titleGroup></publicationMeta><publicationMeta level="part" position="80"><doi origin="wiley" registered="yes">10.1002/jnr.v85:8</doi><numberingGroup><numbering type="journalVolume" number="85">85</numbering><numbering type="journalIssue">8</numbering></numberingGroup><coverDate startDate="2007-06">June 2007</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="230" status="forIssue"><doi origin="wiley" registered="yes">10.1002/jnr.21310</doi><idGroup><id type="unit" value="JNR21310"></id></idGroup><countGroup><count type="pageTotal" number="7"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2007 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="2006-11-26"></event><event type="manuscriptRevised" date="2007-02-02"></event><event type="manuscriptAccepted" date="2007-02-05"></event><event type="publishedOnlineEarlyUnpaginated" date="2007-04-26"></event><event type="firstOnline" date="2007-04-26"></event><event type="publishedOnlineFinalForm" date="2007-05-18"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.2 mode:FullText source:FullText result:FullText" date="2010-03-15"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-31"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-30"></event></eventGroup><numberingGroup><numbering type="pageFirst">1819</numbering><numbering type="pageLast">1825</numbering></numberingGroup><correspondenceTo>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Yoshino‐cho 1‐403, Kita‐ku, Saitama‐shi, Saitama 331‐9530, Japan</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:JNR.JNR21310.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="4"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="26"></count><count type="wordTotal" number="3630"></count></countGroup><titleGroup><title type="main" xml:lang="en">Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein</title><title type="short" xml:lang="en">Phosphorylation of Synuclein in Tg Mice</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1" noteRef="#fn1"><personName><givenNames>Masaki</givenNames><familyName>Wakamatsu</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1" noteRef="#fn1"><personName><givenNames>Aiko</givenNames><familyName>Ishii</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Yuriko</givenNames><familyName>Ukai</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Junko</givenNames><familyName>Sakagami</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Shingo</givenNames><familyName>Iwata</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Mieko</givenNames><familyName>Ono</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Kayo</givenNames><familyName>Matsumoto</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Atsushi</givenNames><familyName>Nakamura</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1" currentRef="#curr1"><personName><givenNames>Norihiro</givenNames><familyName>Tada</familyName></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Kazuto</givenNames><familyName>Kobayashi</familyName></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Takeshi</givenNames><familyName>Iwatsubo</familyName></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>Makoto</givenNames><familyName>Yoshimoto</familyName></personName><contactDetails><email>m.yoshimoto@po.rd.taisho.co.jp</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="JP" type="organization"><unparsedAffiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="JP" type="organization"><unparsedAffiliation>Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="JP" type="organization"><unparsedAffiliation>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan</unparsedAffiliation></affiliation><affiliation xml:id="curr1" countryCode="JP"><unparsedAffiliation>Atopy Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113‐8421, Japan</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">α‐synuclein</keyword><keyword xml:id="kwd2">transgenic mouse</keyword><keyword xml:id="kwd3">tyrosine hydroxylase</keyword><keyword xml:id="kwd4">phosphorylation</keyword><keyword xml:id="kwd5">dopaminergic neuron</keyword><keyword xml:id="kwd6">casein kinase</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Parkinson's disease is neuropathologically characterized by the presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice that expressed human α‐synuclein carrying an Ala53Thr point mutation (hα‐syn140m) under the control of the rat tyrosine hydroxylase promoter and found that hα‐syn140m was localized not only in the cytoplasm but also in the nuclei of mesencephalic dopaminergic neurons. In the present study, we carried out immunohistochemical analysis of the brain of Tg mice using anti‐PSer129, an antibody that specifically recognizes α‐synuclein phosphorylated at Ser129. The antibody detected only phosphorylated hα‐syn140m, whereas phosphorylation of endogenous α‐synuclein, if any, was below the detection limit of the method employed. The analysis showed that approximately one‐third of the hα‐syn140m‐positive neurons in the midbrain of heterozygous Tg mice were concomitantly reactive to anti‐PSer129. The ratio almost doubled in homozygotes, indicating that the phosphorylation level depends directly on the amount of substrate. In addition, the ratio did not change at least up to 48 weeks of age. These data strongly suggest that hα‐syn140m underwent constitutive phosphorylation and that the phosphorylation level was maintained to a certain level until the aged stages. Remarkably, hα‐syn140m localized in the nuclei seemed to be preferentially phosphorylated compared with that in the cytoplasm. Among kinases that have been reported to be involved in the phosphorylation of α‐synuclein, the β subunit of casein kinase‐2 was detected in the nuclei by immunohistochemistry. These data imply that at least casein kinase‐2 is involved in the phosphorylation of hα‐syn140m in the Tg mice. © 2007 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>The first two authors contributed equally to this work.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Phosphorylation of Synuclein in Tg Mice</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Accumulation of phosphorylated α‐synuclein in dopaminergic neurons of transgenic mice that express human α‐synuclein</title></titleInfo><name type="personal"><namePart type="given">Masaki</namePart><namePart type="family">Wakamatsu</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><description>The first two authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aiko</namePart><namePart type="family">Ishii</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><description>The first two authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yuriko</namePart><namePart type="family">Ukai</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Junko</namePart><namePart type="family">Sakagami</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shingo</namePart><namePart type="family">Iwata</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mieko</namePart><namePart type="family">Ono</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kayo</namePart><namePart type="family">Matsumoto</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Atsushi</namePart><namePart type="family">Nakamura</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Norihiro</namePart><namePart type="family">Tada</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><affiliation>Current Address: Atopy Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113‐8421, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kazuto</namePart><namePart type="family">Kobayashi</namePart><affiliation>Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Takeshi</namePart><namePart type="family">Iwatsubo</namePart><affiliation>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Makoto</namePart><namePart type="family">Yoshimoto</namePart><affiliation>Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><description>Correspondence: Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Yoshino‐cho 1‐403, Kita‐ku, Saitama‐shi, Saitama 331‐9530, Japan</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2007-06</dateIssued><dateCaptured encoding="w3cdtf">2006-11-26</dateCaptured><dateValid encoding="w3cdtf">2007-02-05</dateValid><copyrightDate encoding="w3cdtf">2007</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">4</extent><extent unit="references">26</extent><extent unit="words">3630</extent></physicalDescription><abstract lang="en">Parkinson's disease is neuropathologically characterized by the presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice that expressed human α‐synuclein carrying an Ala53Thr point mutation (hα‐syn140m) under the control of the rat tyrosine hydroxylase promoter and found that hα‐syn140m was localized not only in the cytoplasm but also in the nuclei of mesencephalic dopaminergic neurons. In the present study, we carried out immunohistochemical analysis of the brain of Tg mice using anti‐PSer129, an antibody that specifically recognizes α‐synuclein phosphorylated at Ser129. The antibody detected only phosphorylated hα‐syn140m, whereas phosphorylation of endogenous α‐synuclein, if any, was below the detection limit of the method employed. The analysis showed that approximately one‐third of the hα‐syn140m‐positive neurons in the midbrain of heterozygous Tg mice were concomitantly reactive to anti‐PSer129. The ratio almost doubled in homozygotes, indicating that the phosphorylation level depends directly on the amount of substrate. In addition, the ratio did not change at least up to 48 weeks of age. These data strongly suggest that hα‐syn140m underwent constitutive phosphorylation and that the phosphorylation level was maintained to a certain level until the aged stages. Remarkably, hα‐syn140m localized in the nuclei seemed to be preferentially phosphorylated compared with that in the cytoplasm. Among kinases that have been reported to be involved in the phosphorylation of α‐synuclein, the β subunit of casein kinase‐2 was detected in the nuclei by immunohistochemistry. These data imply that at least casein kinase‐2 is involved in the phosphorylation of hα‐syn140m in the Tg mice. © 2007 Wiley‐Liss, Inc.</abstract><subject lang="en"><genre>Keywords</genre><topic>α‐synuclein</topic><topic>transgenic mouse</topic><topic>tyrosine hydroxylase</topic><topic>phosphorylation</topic><topic>dopaminergic neuron</topic><topic>casein kinase</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neuroscience Research</title></titleInfo><titleInfo type="abbreviated"><title>J. Neurosci. Res.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0360-4012</identifier><identifier type="eISSN">1097-4547</identifier><identifier type="DOI">10.1002/(ISSN)1097-4547</identifier><identifier type="PublisherID">JNR</identifier><part><date>2007</date><detail type="volume"><caption>vol.</caption><number>85</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>1819</start><end>1825</end><total>7</total></extent></part></relatedItem><identifier type="istex">55D6D880668A55AC824B971B68CB3696639CC8B6</identifier><identifier type="DOI">10.1002/jnr.21310</identifier><identifier type="ArticleID">JNR21310</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2007 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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