Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system
Identifieur interne : 001A57 ( Main/Corpus ); précédent : 001A56; suivant : 001A58Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system
Auteurs : Carl Rosenblad ; Biljana Georgievska ; Deniz KirikSource :
- European Journal of Neuroscience [ 0953-816X ] ; 2003-01.
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- KwdEn :
Abstract
Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long‐term glial cell line‐derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25–100‐fold increase above control vector‐ or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39–72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase‐immunoreactive innervation in the striatum was reduced by 25–52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2‐immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. Taken together our findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur.
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DOI: 10.1046/j.1460-9568.2003.02456.x
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To investigate the effect of long‐term glial cell line‐derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25–100‐fold increase above control vector‐ or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39–72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase‐immunoreactive innervation in the striatum was reduced by 25–52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2‐immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. 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To investigate the effect of long‐term glial cell line‐derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25–100‐fold increase above control vector‐ or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39–72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase‐immunoreactive innervation in the striatum was reduced by 25–52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2‐immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. 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To investigate the effect of long‐term glial cell line‐derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25–100‐fold increase above control vector‐ or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39–72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase‐immunoreactive innervation in the striatum was reduced by 25–52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2‐immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. 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E‐mail: <email>cro@nsgene.dk</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:EJN.EJN2456.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 12 July 2002, revised 1 October 2002, accepted 8 November 2002</unparsedEditorialHistory><countGroup><count type="figureTotal" number="7"></count><count type="tableTotal" number="0"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="40"></count><count type="wordTotal" number="5726"></count><count type="linksPubMed" number="0"></count><count type="linksCrossRef" number="0"></count></countGroup><titleGroup><title type="main">Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system</title><title type="shortAuthors">C. Rosenblad <i>et al</i>.</title><title type="short">Long‐term GDNF treatment of intact dopamine neurons</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><givenNames>Carl</givenNames><familyName>Rosenblad</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a2"><personName><givenNames>Biljana</givenNames><familyName>Georgievska</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a2"><personName><givenNames>Deniz</givenNames><familyName>Kirik</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="DK"><unparsedAffiliation>NsGene A/S, Ballerup, Denmark</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="SE"><unparsedAffiliation>Wallenberg Neuroscience Centre, Department Physiological Sciences, Lund University, Lund, Sweden</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">autoradiography</keyword><keyword xml:id="k2">lentivirus</keyword><keyword xml:id="k3">rat</keyword><keyword xml:id="k4">striatum</keyword><keyword xml:id="k5">substantia nigra </keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long‐term glial cell line‐derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25–100‐fold increase above control vector‐ or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39–72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase‐immunoreactive innervation in the striatum was reduced by 25–52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2‐immunoreactivity or [<sup>3</sup>H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [<sup>3</sup>H]SCH23390 and [<sup>3</sup>H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. Taken together our findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system</title></titleInfo><titleInfo type="abbreviated"><title>Long‐term GDNF treatment of intact dopamine neurons</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system</title></titleInfo><name type="personal"><namePart type="given">Carl</namePart><namePart type="family">Rosenblad</namePart><affiliation>NsGene A/S, Ballerup, Denmark</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Biljana</namePart><namePart type="family">Georgievska</namePart><affiliation>Wallenberg Neuroscience Centre, Department Physiological Sciences, Lund University, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Deniz</namePart><namePart type="family">Kirik</namePart><affiliation>Wallenberg Neuroscience Centre, Department Physiological Sciences, Lund University, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Science, Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2003-01</dateIssued><edition>Received 12 July 2002, revised 1 October 2002, accepted 8 November 2002</edition><copyrightDate encoding="w3cdtf">2003</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">7</extent><extent unit="references">40</extent><extent unit="words">5726</extent></physicalDescription><abstract lang="en">Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long‐term glial cell line‐derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25–100‐fold increase above control vector‐ or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39–72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase‐immunoreactive innervation in the striatum was reduced by 25–52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2‐immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. Taken together our findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur.</abstract><subject lang="en"><genre>Keywords</genre><topic>autoradiography</topic><topic>lentivirus</topic><topic>rat</topic><topic>striatum</topic><topic>substantia nigra</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>2003</date><detail type="volume"><caption>vol.</caption><number>17</number></detail><detail type="issue"><caption>no.</caption><number>2</number></detail><extent unit="pages"><start>260</start><end>270</end></extent></part></relatedItem><identifier type="istex">1EF5C82274C6D759E87F42DFCB29E09AE0A17FBF</identifier><identifier type="DOI">10.1046/j.1460-9568.2003.02456.x</identifier><identifier type="ArticleID">EJN2456</identifier><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Science, Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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