Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease
Identifieur interne : 001915 ( Main/Corpus ); précédent : 001914; suivant : 001916Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease
Auteurs : Rebecca E. Colebrooke ; Trevor Humby ; Patrick J. Lynch ; Daniel P. Mcgowan ; Jing Xia ; Piers C. EmsonSource :
- European Journal of Neuroscience [ 0953-816X ] ; 2006-11.
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- KwdEn :
Abstract
Dopamine cytotoxicity is thought to contribute towards the selective loss of substantia nigra pars compacta dopamine neurons and disease progression in Parkinson's disease. However, the long‐term toxicity of dopamine in vivo has not previously been established. The vesicular monoamine transporter 2 (VMAT2) sequesters monoamines into synaptic vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of monoamine neurotransmitters below potentially toxic thresholds. The homozygous VMAT2‐hypomorphic mouse has an insertion in the VMAT2 gene (Slc18a2). Consequently, VMAT2‐deficient mice (VD–/–) have an ∼ 95% reduction in VMAT2 expression and an equivalent level of dopamine depletion in the striatum which results in moderate motor impairment. Here, we show that L‐DOPA induces locomotor hyperactivity in VD–/– mice and reverses the deficit in motor coordination and balance as tested with the rotarod. We report that evidence for cytosolic accumulation of dopamine in substantia nigra neurons in these mice is two‐fold: firstly, there is reduced phosphorylation of tyrosine hydroxylase at the residue associated with catechol feedback inhibition; and, secondly, there are increased rates of dopamine turnover at 6, 12 and 24 months of age. These animals exhibit a progressive decline in striatal monoamine levels and rotarod performance with increasing age. However, despite these data, there was no loss of nigral dopamine neurons as estimated by quantification of tyrosine hydroxylase‐immunoreactive cells in the substantia nigra pars compacta of old VD–/– mice (24‐month‐old), implying that these age‐dependent manifestations may be due to senescence alone.
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DOI: 10.1111/j.1460-9568.2006.05143.x
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However, the long‐term toxicity of dopamine in vivo has not previously been established. The vesicular monoamine transporter 2 (VMAT2) sequesters monoamines into synaptic vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of monoamine neurotransmitters below potentially toxic thresholds. The homozygous VMAT2‐hypomorphic mouse has an insertion in the VMAT2 gene (Slc18a2). Consequently, VMAT2‐deficient mice (VD–/–) have an ∼ 95% reduction in VMAT2 expression and an equivalent level of dopamine depletion in the striatum which results in moderate motor impairment. Here, we show that L‐DOPA induces locomotor hyperactivity in VD–/– mice and reverses the deficit in motor coordination and balance as tested with the rotarod. We report that evidence for cytosolic accumulation of dopamine in substantia nigra neurons in these mice is two‐fold: firstly, there is reduced phosphorylation of tyrosine hydroxylase at the residue associated with catechol feedback inhibition; and, secondly, there are increased rates of dopamine turnover at 6, 12 and 24 months of age. These animals exhibit a progressive decline in striatal monoamine levels and rotarod performance with increasing age. However, despite these data, there was no loss of nigral dopamine neurons as estimated by quantification of tyrosine hydroxylase‐immunoreactive cells in the substantia nigra pars compacta of old VD–/– mice (24‐month‐old), implying that these age‐dependent manifestations may be due to senescence alone.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Rebecca E. 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We report that evidence for cytosolic accumulation of dopamine in substantia nigra neurons in these mice is two‐fold: firstly, there is reduced phosphorylation of tyrosine hydroxylase at the residue associated with catechol feedback inhibition; and, secondly, there are increased rates of dopamine turnover at 6, 12 and 24 months of age. These animals exhibit a progressive decline in striatal monoamine levels and rotarod performance with increasing age. 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We report that evidence for cytosolic accumulation of dopamine in substantia nigra neurons in these mice is two‐fold: firstly, there is reduced phosphorylation of tyrosine hydroxylase at the residue associated with catechol feedback inhibition; and, secondly, there are increased rates of dopamine turnover at 6, 12 and 24 months of age. These animals exhibit a progressive decline in striatal monoamine levels and rotarod performance with increasing age. However, despite these data, there was no loss of nigral dopamine neurons as estimated by quantification of tyrosine hydroxylase‐immunoreactive cells in the substantia nigra pars compacta of old VD–/– mice (24‐month‐old), implying that these age‐dependent manifestations may be due to senescence alone.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>dopamine</term></item><item><term>L‐DOPA</term></item><item><term>locomotor activity</term></item><item><term>VMAT2</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2006-11">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/C79054925213DEA25DD03EA184A9D69B3C3B0D92/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>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1460-9568</doi><issn type="print">0953-816X</issn><issn type="electronic">1460-9568</issn><idGroup><id type="product" value="EJN"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="EUROPEAN JOURNAL OF NEUROSCIENCE">European Journal of Neuroscience</title></titleGroup></publicationMeta><publicationMeta level="part" position="11109"><doi origin="wiley">10.1111/ejn.2006.24.issue-9</doi><numberingGroup><numbering type="journalVolume" number="24">24</numbering><numbering type="journalIssue" number="9">9</numbering></numberingGroup><coverDate startDate="2006-11">November 2006</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="20" status="forIssue"><doi origin="wiley">10.1111/j.1460-9568.2006.05143.x</doi><idGroup><id type="unit" value="EJN5143"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="tocHeading1">Research Reports</title></titleGroup><eventGroup><event type="firstOnline" date="2006-11-13"></event><event type="publishedOnlineFinalForm" date="2006-11-13"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.22 mode:FullText" date="2010-10-06"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-12"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-16"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="2622">2622</numbering><numbering type="pageLast" number="2630">2630</numbering></numberingGroup><correspondenceTo>Dr Piers C. Emson, as above. E‐mail: <email>piers.emson@bbsrc.ac.uk</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:EJN.EJN5143.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 1 June 2006, revised 2 August 2006, accepted 28 August 2006</unparsedEditorialHistory><countGroup><count type="figureTotal" number="6"></count><count type="tableTotal" number="3"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="55"></count><count type="wordTotal" number="5586"></count><count type="linksPubMed" number="0"></count><count type="linksCrossRef" number="0"></count></countGroup><titleGroup><title type="main">Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease</title><title type="shortAuthors">R. E. Colebrooke <i>et al.</i></title><title type="short">Age‐dependent manifestations in a model of Parkinsonism</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><givenNames>Rebecca E.</givenNames><familyName>Colebrooke</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1 #a2"><personName><givenNames>Trevor</givenNames><familyName>Humby</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1"><personName><givenNames>Patrick J.</givenNames><familyName>Lynch</familyName></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1"><personName><givenNames>Daniel P.</givenNames><familyName>McGowan</familyName></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a1"><personName><givenNames>Jing</givenNames><familyName>Xia</familyName></personName></creator><creator creatorRole="author" xml:id="cr6" affiliationRef="#a1"><personName><givenNames>Piers C.</givenNames><familyName>Emson</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="GB"><unparsedAffiliation>Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="GB"><unparsedAffiliation>School of Psychology and Department of Psychological Medicine, Cardiff University, Cardiff, UK</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">dopamine</keyword><keyword xml:id="k2">L‐DOPA</keyword><keyword xml:id="k3">locomotor activity</keyword><keyword xml:id="k4">VMAT2</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Dopamine cytotoxicity is thought to contribute towards the selective loss of substantia nigra pars compacta dopamine neurons and disease progression in Parkinson's disease. However, the long‐term toxicity of dopamine <i>in vivo</i> has not previously been established. The vesicular monoamine transporter 2 (VMAT2) sequesters monoamines into synaptic vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of monoamine neurotransmitters below potentially toxic thresholds. The homozygous VMAT2‐hypomorphic mouse has an insertion in the VMAT2 gene (<i>Slc18a2</i>). Consequently, VMAT2‐deficient mice (VD<sup>–/–</sup>) have an ∼ 95% reduction in VMAT2 expression and an equivalent level of dopamine depletion in the striatum which results in moderate motor impairment. Here, we show that L‐DOPA induces locomotor hyperactivity in VD<sup>–/–</sup> mice and reverses the deficit in motor coordination and balance as tested with the rotarod. We report that evidence for cytosolic accumulation of dopamine in substantia nigra neurons in these mice is two‐fold: firstly, there is reduced phosphorylation of tyrosine hydroxylase at the residue associated with catechol feedback inhibition; and, secondly, there are increased rates of dopamine turnover at 6, 12 and 24 months of age. These animals exhibit a progressive decline in striatal monoamine levels and rotarod performance with increasing age. However, despite these data, there was no loss of nigral dopamine neurons as estimated by quantification of tyrosine hydroxylase‐immunoreactive cells in the substantia nigra pars compacta of old VD<sup>–/–</sup> mice (24‐month‐old), implying that these age‐dependent manifestations may be due to senescence alone.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease</title></titleInfo><titleInfo type="abbreviated"><title>Age‐dependent manifestations in a model of Parkinsonism</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Rebecca E.</namePart><namePart type="family">Colebrooke</namePart><affiliation>Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Trevor</namePart><namePart type="family">Humby</namePart><affiliation>Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK</affiliation><affiliation>School of Psychology and Department of Psychological Medicine, Cardiff University, Cardiff, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrick J.</namePart><namePart type="family">Lynch</namePart><affiliation>Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel P.</namePart><namePart type="family">McGowan</namePart><affiliation>Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jing</namePart><namePart type="family">Xia</namePart><affiliation>Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Piers C.</namePart><namePart type="family">Emson</namePart><affiliation>Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2006-11</dateIssued><edition>Received 1 June 2006, revised 2 August 2006, accepted 28 August 2006</edition><copyrightDate encoding="w3cdtf">2006</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">6</extent><extent unit="tables">3</extent><extent unit="references">55</extent><extent unit="words">5586</extent></physicalDescription><abstract lang="en">Dopamine cytotoxicity is thought to contribute towards the selective loss of substantia nigra pars compacta dopamine neurons and disease progression in Parkinson's disease. However, the long‐term toxicity of dopamine in vivo has not previously been established. The vesicular monoamine transporter 2 (VMAT2) sequesters monoamines into synaptic vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of monoamine neurotransmitters below potentially toxic thresholds. The homozygous VMAT2‐hypomorphic mouse has an insertion in the VMAT2 gene (Slc18a2). Consequently, VMAT2‐deficient mice (VD–/–) have an ∼ 95% reduction in VMAT2 expression and an equivalent level of dopamine depletion in the striatum which results in moderate motor impairment. Here, we show that L‐DOPA induces locomotor hyperactivity in VD–/– mice and reverses the deficit in motor coordination and balance as tested with the rotarod. We report that evidence for cytosolic accumulation of dopamine in substantia nigra neurons in these mice is two‐fold: firstly, there is reduced phosphorylation of tyrosine hydroxylase at the residue associated with catechol feedback inhibition; and, secondly, there are increased rates of dopamine turnover at 6, 12 and 24 months of age. These animals exhibit a progressive decline in striatal monoamine levels and rotarod performance with increasing age. However, despite these data, there was no loss of nigral dopamine neurons as estimated by quantification of tyrosine hydroxylase‐immunoreactive cells in the substantia nigra pars compacta of old VD–/– mice (24‐month‐old), implying that these age‐dependent manifestations may be due to senescence alone.</abstract><subject lang="en"><genre>Keywords</genre><topic>dopamine</topic><topic>L‐DOPA</topic><topic>locomotor activity</topic><topic>VMAT2</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Neuroscience</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0953-816X</identifier><identifier type="eISSN">1460-9568</identifier><identifier type="DOI">10.1111/(ISSN)1460-9568</identifier><identifier type="PublisherID">EJN</identifier><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>24</number></detail><detail type="issue"><caption>no.</caption><number>9</number></detail><extent unit="pages"><start>2622</start><end>2630</end><total>9</total></extent></part></relatedItem><identifier type="istex">C79054925213DEA25DD03EA184A9D69B3C3B0D92</identifier><identifier type="DOI">10.1111/j.1460-9568.2006.05143.x</identifier><identifier type="ArticleID">EJN5143</identifier><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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