Mortalin inhibition in experimental Parkinson's disease
Identifieur interne : 000293 ( Istex/Corpus ); précédent : 000292; suivant : 000294Mortalin inhibition in experimental Parkinson's disease
Auteurs : Davide Chiasserini ; Alessandro Tozzi ; Antonio De Iure ; Michela Tantucci ; Federica Susta ; Pier Luigi Orvietani ; Keizo Koya ; Luciano Binaglia ; Paolo CalabresiSource :
- Movement Disorders [ 0885-3185 ] ; 2011-08-01.
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Abstract
Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6‐hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT‐077, a rhodamine‐123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham‐operated, and 6‐hydroxydopamine–denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6‐hydroxydopamine–treated rats in comparison with sham‐operated animals. MKT‐077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT‐077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. © 2011 Movement Disorder Society
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DOI: 10.1002/mds.23647
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Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-08-01">2011-08-01</date><biblScope unit="vol">26</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1639">1639</biblScope><biblScope unit="page" to="1647">1647</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">50D32C6A650908F0A66D37519E1B249E0D005A43</idno><idno type="DOI">10.1002/mds.23647</idno><idno type="ArticleID">MDS23647</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>6‐hydroxydopamine</term><term>Parkinson's disease</term><term>heat shock protein</term><term>mitochondria</term><term>mortalin</term><term>rotenone</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6‐hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT‐077, a rhodamine‐123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham‐operated, and 6‐hydroxydopamine–denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6‐hydroxydopamine–treated rats in comparison with sham‐operated animals. MKT‐077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT‐077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. © 2011 Movement Disorder Society</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Davide Chiasserini PhD</name><affiliations><json:string>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</json:string><json:string>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</json:string></affiliations></json:item><json:item><name>Alessandro Tozzi PhD</name><affiliations><json:string>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</json:string><json:string>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</json:string></affiliations></json:item><json:item><name>Antonio de Iure PhD</name><affiliations><json:string>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</json:string><json:string>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</json:string></affiliations></json:item><json:item><name>Michela Tantucci PhD</name><affiliations><json:string>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</json:string></affiliations></json:item><json:item><name>Federica Susta PhD</name><affiliations><json:string>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</json:string></affiliations></json:item><json:item><name>Pier Luigi Orvietani MSc</name><affiliations><json:string>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</json:string></affiliations></json:item><json:item><name>Keizo Koya PhD</name><affiliations><json:string>Synta Pharmaceuticals Corp., Lexington, Massachusetts, USA</json:string></affiliations></json:item><json:item><name>Luciano Binaglia PhD</name><affiliations><json:string>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</json:string></affiliations></json:item><json:item><name>Paolo Calabresi MD</name><affiliations><json:string>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</json:string><json:string>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>mortalin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>6‐hydroxydopamine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>rotenone</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>mitochondria</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>heat shock protein</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6‐hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT‐077, a rhodamine‐123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham‐operated, and 6‐hydroxydopamine–denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6‐hydroxydopamine–treated rats in comparison with sham‐operated animals. MKT‐077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT‐077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. © 2011 Movement Disorder Society</abstract><qualityIndicators><score>7.796</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1795</abstractCharCount><pdfWordCount>5373</pdfWordCount><pdfCharCount>36453</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>233</abstractWordCount></qualityIndicators><title>Mortalin inhibition in experimental Parkinson's disease</title><genre><json:string>Serial article</json:string></genre><host><volume>26</volume><pages><total>9</total><last>1647</last><first>1639</first></pages><issn><json:string>0885-3185</json:string></issn><issue>9</issue><subject><json:item><value>Research Article</value></json:item></subject><genre></genre><language><json:string>unknown</json:string></language><title>Movement Disorders</title><doi><json:string>10.1002/(ISSN)1531-8257</json:string></doi></host><publicationDate>2011</publicationDate><copyrightDate>2011</copyrightDate><doi><json:string>10.1002/mds.23647</json:string></doi><id>50D32C6A650908F0A66D37519E1B249E0D005A43</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/50D32C6A650908F0A66D37519E1B249E0D005A43/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/50D32C6A650908F0A66D37519E1B249E0D005A43/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/50D32C6A650908F0A66D37519E1B249E0D005A43/fulltext/tei"><teiHeader type="text"><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Mortalin inhibition in experimental Parkinson's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>Wiley Subscription Services, Inc., A Wiley Company</p></availability><date>2011</date></publicationStmt><notesStmt><note type="content">*Relevant conflicts of interest/financial disclosures: Nothing to report. The present work was supported by grants from the European Community (EC) contract number 222918 (REPLACES) FP7—Thematic priority HEALTH (to P.C.), Progetto Strategico 2007 (to P.C.), Progetti Finalizzati Multicentrici Programma Neuroscienze Compagnia di San Paolo (to P.C.), and Progetti di Ricerca di Interesse Nazionale (PRIN 2008; to P.C.). Full financial disclosures and author roles may be found in the online version of this article.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Mortalin inhibition in experimental Parkinson's disease</title><author><persName><forename type="first">Davide</forename><surname>Chiasserini</surname><roleName type="degree">PhD</roleName></persName><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation></author><author><persName><forename type="first">Alessandro</forename><surname>Tozzi</surname><roleName type="degree">PhD</roleName></persName><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation></author><author><persName><forename type="first">Antonio</forename><surname>de Iure</surname><roleName type="degree">PhD</roleName></persName><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation></author><author><persName><forename type="first">Michela</forename><surname>Tantucci</surname><roleName type="degree">PhD</roleName></persName><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation></author><author><persName><forename type="first">Federica</forename><surname>Susta</surname><roleName type="degree">PhD</roleName></persName><affiliation>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</affiliation></author><author><persName><forename type="first">Pier Luigi</forename><surname>Orvietani</surname><roleName type="degree">MSc</roleName></persName><affiliation>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</affiliation></author><author><persName><forename type="first">Keizo</forename><surname>Koya</surname><roleName type="degree">PhD</roleName></persName><affiliation>Synta Pharmaceuticals Corp., Lexington, Massachusetts, USA</affiliation></author><author><persName><forename type="first">Luciano</forename><surname>Binaglia</surname><roleName type="degree">PhD</roleName></persName><affiliation>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</affiliation></author><author><persName><forename type="first">Paolo</forename><surname>Calabresi</surname><roleName type="degree">MD</roleName></persName><note type="correspondence"><p>Correspondence: Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy</p></note><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-08-01"></date><biblScope unit="vol">26</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1639">1639</biblScope><biblScope unit="page" to="1647">1647</biblScope></imprint></monogr><idno type="istex">50D32C6A650908F0A66D37519E1B249E0D005A43</idno><idno type="DOI">10.1002/mds.23647</idno><idno type="ArticleID">MDS23647</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6‐hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT‐077, a rhodamine‐123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham‐operated, and 6‐hydroxydopamine–denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6‐hydroxydopamine–treated rats in comparison with sham‐operated animals. MKT‐077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT‐077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. © 2011 Movement Disorder Society</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>mortalin</term></item><item><term>Parkinson's disease</term></item><item><term>6‐hydroxydopamine</term></item><item><term>rotenone</term></item><item><term>mitochondria</term></item><item><term>heat shock protein</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="2010-11-11">Received</change><change when="2010-12-29">Registration</change><change when="2011-08-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/50D32C6A650908F0A66D37519E1B249E0D005A43/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)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="short">Mov. Disord.</title></titleGroup></publicationMeta><publicationMeta level="part" position="90"><doi origin="wiley" registered="yes">10.1002/mds.v26.9</doi><numberingGroup><numbering type="journalVolume" number="26">26</numbering><numbering type="journalIssue">9</numbering></numberingGroup><coverDate startDate="2011-08-01">1 August 2011</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="110" status="forIssue"><doi origin="wiley" registered="yes">10.1002/mds.23647</doi><idGroup><id type="unit" value="MDS23647"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2011 Movement Disorder Society</copyright><eventGroup><event type="manuscriptReceived" date="2010-11-11"></event><event type="manuscriptRevised" date="2010-12-20"></event><event type="manuscriptAccepted" date="2010-12-29"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:3.0.1 mode:FullText" date="2011-12-16"></event><event type="publishedOnlineEarlyUnpaginated" date="2011-05-03"></event><event type="publishedOnlineFinalForm" date="2011-08-09"></event><event type="firstOnline" date="2011-05-03"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-02-02"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-31"></event></eventGroup><numberingGroup><numbering type="pageFirst">1639</numbering><numbering type="pageLast">1647</numbering></numberingGroup><correspondenceTo>Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:MDS.MDS23647.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="1"></count><count type="referenceTotal" number="53"></count><count type="wordTotal" number="7466"></count></countGroup><titleGroup><title type="main" xml:lang="en">Mortalin inhibition in experimental Parkinson's disease<link href="#fn1"></link></title><title type="short" xml:lang="en">Mortalin in Experimental Parkinsonism</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Davide</givenNames><familyName>Chiasserini</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Alessandro</givenNames><familyName>Tozzi</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Antonio</givenNames><familyName>de Iure</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Michela</givenNames><familyName>Tantucci</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Federica</givenNames><familyName>Susta</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Pier Luigi</givenNames><familyName>Orvietani</familyName><degrees>MSc</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Keizo</givenNames><familyName>Koya</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Luciano</givenNames><familyName>Binaglia</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Paolo</givenNames><familyName>Calabresi</familyName><degrees>MD</degrees></personName><contactDetails><email>calabre@unipg.it</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="IT" type="organization"><unparsedAffiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="IT" type="organization"><unparsedAffiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="IT" type="organization"><unparsedAffiliation>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>Synta Pharmaceuticals Corp., Lexington, Massachusetts, USA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">mortalin</keyword><keyword xml:id="kwd2">Parkinson's disease</keyword><keyword xml:id="kwd3">6‐hydroxydopamine</keyword><keyword xml:id="kwd4">rotenone</keyword><keyword xml:id="kwd5">mitochondria</keyword><keyword xml:id="kwd6">heat shock protein</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6‐hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT‐077, a rhodamine‐123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham‐operated, and 6‐hydroxydopamine–denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6‐hydroxydopamine–treated rats in comparison with sham‐operated animals. MKT‐077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT‐077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. © 2011 Movement Disorder Society</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p><b>Relevant conflicts of interest/financial disclosures:</b> Nothing to report. The present work was supported by grants from the European Community (EC) contract number 222918 (REPLACES) FP7—Thematic priority HEALTH (to P.C.), Progetto Strategico 2007 (to P.C.), Progetti Finalizzati Multicentrici Programma Neuroscienze Compagnia di San Paolo (to P.C.), and Progetti di Ricerca di Interesse Nazionale (PRIN 2008; to P.C.). Full financial disclosures and author roles may be found in the online version of this article.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><!--Version 0.6 générée le 3-12-2015--><mods version="3.6"><titleInfo lang="en"><title>Mortalin inhibition in experimental Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Mortalin in Experimental Parkinsonism</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Mortalin inhibition in experimental Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Davide</namePart><namePart type="family">Chiasserini</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alessandro</namePart><namePart type="family">Tozzi</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Antonio</namePart><namePart type="family">de Iure</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michela</namePart><namePart type="family">Tantucci</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Federica</namePart><namePart type="family">Susta</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Pier Luigi</namePart><namePart type="family">Orvietani</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Keizo</namePart><namePart type="family">Koya</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Synta Pharmaceuticals Corp., Lexington, Massachusetts, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Luciano</namePart><namePart type="family">Binaglia</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paolo</namePart><namePart type="family">Calabresi</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy</affiliation><affiliation>Fondazione S. Lucia—I.R.C.C.S., Rome, Italy</affiliation><description>Correspondence: Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre authority="originalCategForm">article</genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2011-08-01</dateIssued><dateCaptured encoding="w3cdtf">2010-11-11</dateCaptured><dateValid encoding="w3cdtf">2010-12-29</dateValid><copyrightDate encoding="w3cdtf">2011</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">3</extent><extent unit="tables">1</extent><extent unit="references">53</extent><extent unit="words">7466</extent></physicalDescription><abstract lang="en">Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6‐hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT‐077, a rhodamine‐123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham‐operated, and 6‐hydroxydopamine–denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6‐hydroxydopamine–treated rats in comparison with sham‐operated animals. MKT‐077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT‐077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. © 2011 Movement Disorder Society</abstract><note type="content">*Relevant conflicts of interest/financial disclosures: Nothing to report. The present work was supported by grants from the European Community (EC) contract number 222918 (REPLACES) FP7—Thematic priority HEALTH (to P.C.), Progetto Strategico 2007 (to P.C.), Progetti Finalizzati Multicentrici Programma Neuroscienze Compagnia di San Paolo (to P.C.), and Progetti di Ricerca di Interesse Nazionale (PRIN 2008; to P.C.). Full financial disclosures and author roles may be found in the online version of this article.</note><subject lang="en"><genre>Keywords</genre><topic>mortalin</topic><topic>Parkinson's disease</topic><topic>6‐hydroxydopamine</topic><topic>rotenone</topic><topic>mitochondria</topic><topic>heat shock protein</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title></titleInfo><titleInfo type="abbreviated"><title>Mov. 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