Dopamine D2 receptor knockout mice develop features of Parkinson disease
Identifieur interne : 002E39 ( Main/Corpus ); précédent : 002E38; suivant : 002E40Dopamine D2 receptor knockout mice develop features of Parkinson disease
Auteurs : Rogan B. Tinsley ; Chris R. Bye ; Clare L. Parish ; Angela Tziotis-Vais ; Sonia George ; Janetta G. Culvenor ; Qiao-Xin Li ; Colin L. Masters ; David I. Finkelstein ; Malcolm K. HorneSource :
- Annals of Neurology [ 0364-5134 ] ; 2009-10.
Abstract
Objective: This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α‐synuclein–containing cytoplasmic inclusion of Parkinson disease (PD). Methods: Mice with targeted deletion of the dopamine D2 receptor gene (D2R[−/−]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy. Results: LB‐like cytoplasmic inclusions containing α‐synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D2R(−/−) mice, and were also occasionally seen in aged wild‐type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic α‐synuclein immunoreactivity in SNpc neurons increased with age in both wild‐type and D2R(−/−) mice, most likely because of redistribution of α‐synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D2R(−/−) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc. Interpretation: Increased sprouting and DA turnover, as observed in PD and D2R(−/−) mice, augments LB‐like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy. Ann Neurol 2009;66:472–484
Url:
DOI: 10.1002/ana.21716
Links to Exploration step
ISTEX:00CEA8C9D1AA8C904F6B87067446856884344936Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Dopamine D2 receptor knockout mice develop features of Parkinson disease</title><author><name sortKey="Tinsley, Rogan B" sort="Tinsley, Rogan B" uniqKey="Tinsley R" first="Rogan B." last="Tinsley">Rogan B. Tinsley</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Bye, Chris R" sort="Bye, Chris R" uniqKey="Bye C" first="Chris R." last="Bye">Chris R. Bye</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Parish, Clare L" sort="Parish, Clare L" uniqKey="Parish C" first="Clare L." last="Parish">Clare L. Parish</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Tziotis Ais, Angela" sort="Tziotis Ais, Angela" uniqKey="Tziotis Ais A" first="Angela" last="Tziotis-Vais">Angela Tziotis-Vais</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="George, Sonia" sort="George, Sonia" uniqKey="George S" first="Sonia" last="George">Sonia George</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Culvenor, Janetta G" sort="Culvenor, Janetta G" uniqKey="Culvenor J" first="Janetta G." last="Culvenor">Janetta G. Culvenor</name><affiliation><mods:affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Li, Qiao In" sort="Li, Qiao In" uniqKey="Li Q" first="Qiao-Xin" last="Li">Qiao-Xin Li</name><affiliation><mods:affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Masters, Colin L" sort="Masters, Colin L" uniqKey="Masters C" first="Colin L." last="Masters">Colin L. Masters</name><affiliation><mods:affiliation>Mental Health Research Institute, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Finkelstein, David I" sort="Finkelstein, David I" uniqKey="Finkelstein D" first="David I." last="Finkelstein">David I. Finkelstein</name><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Horne, Malcolm K" sort="Horne, Malcolm K" uniqKey="Horne M" first="Malcolm K." last="Horne">Malcolm K. Horne</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, St Vincent's Hospital, Fitzroy, Australia</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:00CEA8C9D1AA8C904F6B87067446856884344936</idno><date when="2009" year="2009">2009</date><idno type="doi">10.1002/ana.21716</idno><idno type="url">https://api.istex.fr/document/00CEA8C9D1AA8C904F6B87067446856884344936/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">002E39</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Dopamine D2 receptor knockout mice develop features of Parkinson disease</title><author><name sortKey="Tinsley, Rogan B" sort="Tinsley, Rogan B" uniqKey="Tinsley R" first="Rogan B." last="Tinsley">Rogan B. Tinsley</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Bye, Chris R" sort="Bye, Chris R" uniqKey="Bye C" first="Chris R." last="Bye">Chris R. Bye</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Parish, Clare L" sort="Parish, Clare L" uniqKey="Parish C" first="Clare L." last="Parish">Clare L. Parish</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Tziotis Ais, Angela" sort="Tziotis Ais, Angela" uniqKey="Tziotis Ais A" first="Angela" last="Tziotis-Vais">Angela Tziotis-Vais</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="George, Sonia" sort="George, Sonia" uniqKey="George S" first="Sonia" last="George">Sonia George</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Culvenor, Janetta G" sort="Culvenor, Janetta G" uniqKey="Culvenor J" first="Janetta G." last="Culvenor">Janetta G. Culvenor</name><affiliation><mods:affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Li, Qiao In" sort="Li, Qiao In" uniqKey="Li Q" first="Qiao-Xin" last="Li">Qiao-Xin Li</name><affiliation><mods:affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Masters, Colin L" sort="Masters, Colin L" uniqKey="Masters C" first="Colin L." last="Masters">Colin L. Masters</name><affiliation><mods:affiliation>Mental Health Research Institute, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Finkelstein, David I" sort="Finkelstein, David I" uniqKey="Finkelstein D" first="David I." last="Finkelstein">David I. Finkelstein</name><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation></author><author><name sortKey="Horne, Malcolm K" sort="Horne, Malcolm K" uniqKey="Horne M" first="Malcolm K." last="Horne">Malcolm K. Horne</name><affiliation><mods:affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, St Vincent's Hospital, Fitzroy, Australia</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-10">2009-10</date><biblScope unit="volume">66</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="472">472</biblScope><biblScope unit="page" to="484">484</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">00CEA8C9D1AA8C904F6B87067446856884344936</idno><idno type="DOI">10.1002/ana.21716</idno><idno type="ArticleID">ANA21716</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α‐synuclein–containing cytoplasmic inclusion of Parkinson disease (PD). Methods: Mice with targeted deletion of the dopamine D2 receptor gene (D2R[−/−]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy. Results: LB‐like cytoplasmic inclusions containing α‐synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D2R(−/−) mice, and were also occasionally seen in aged wild‐type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic α‐synuclein immunoreactivity in SNpc neurons increased with age in both wild‐type and D2R(−/−) mice, most likely because of redistribution of α‐synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D2R(−/−) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc. Interpretation: Increased sprouting and DA turnover, as observed in PD and D2R(−/−) mice, augments LB‐like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy. Ann Neurol 2009;66:472–484</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Rogan B. Tinsley PhD</name><affiliations><json:string>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Chris R. Bye BSc (Hon)</name><affiliations><json:string>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Clare L. Parish PhD</name><affiliations><json:string>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Angela Tziotis‐Vais BSc (Hon)</name><affiliations><json:string>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Sonia George PhD</name><affiliations><json:string>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</json:string><json:string>Department of Pathology, the University of Melbourne, Parkville, Australia</json:string><json:string>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Janetta G. Culvenor PhD</name><affiliations><json:string>Department of Pathology, the University of Melbourne, Parkville, Australia</json:string><json:string>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Qiao‐Xin Li PhD</name><affiliations><json:string>Department of Pathology, the University of Melbourne, Parkville, Australia</json:string><json:string>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Colin L. Masters MD</name><affiliations><json:string>Mental Health Research Institute, Parkville, Australia</json:string></affiliations></json:item><json:item><name>David I. Finkelstein PhD</name><affiliations><json:string>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</json:string></affiliations></json:item><json:item><name>Malcolm K. Horne MD, PhD</name><affiliations><json:string>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</json:string><json:string>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</json:string><json:string>Department of Neurology, St Vincent's Hospital, Fitzroy, Australia</json:string></affiliations></json:item></author><articleId><json:string>ANA21716</json:string></articleId><language><json:string>eng</json:string></language><abstract>Objective: This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α‐synuclein–containing cytoplasmic inclusion of Parkinson disease (PD). Methods: Mice with targeted deletion of the dopamine D2 receptor gene (D2R[−/−]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy. Results: LB‐like cytoplasmic inclusions containing α‐synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D2R(−/−) mice, and were also occasionally seen in aged wild‐type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic α‐synuclein immunoreactivity in SNpc neurons increased with age in both wild‐type and D2R(−/−) mice, most likely because of redistribution of α‐synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D2R(−/−) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc. Interpretation: Increased sprouting and DA turnover, as observed in PD and D2R(−/−) mice, augments LB‐like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy. Ann Neurol 2009;66:472–484</abstract><qualityIndicators><score>7.628</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1584</abstractCharCount><pdfWordCount>7670</pdfWordCount><pdfCharCount>49152</pdfCharCount><pdfPageCount>13</pdfPageCount><abstractWordCount>219</abstractWordCount></qualityIndicators><title>Dopamine D2 receptor knockout mice develop features of Parkinson disease</title><genre><json:string>article</json:string></genre><host><volume>66</volume><publisherId><json:string>ANA</json:string></publisherId><pages><total>13</total><last>484</last><first>472</first></pages><issn><json:string>0364-5134</json:string></issn><issue>4</issue><subject><json:item><value>Original Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8249</json:string></eissn><title>Annals of Neurology</title><doi><json:string>10.1002/(ISSN)1531-8249</json:string></doi></host><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1002/ana.21716</json:string></doi><id>00CEA8C9D1AA8C904F6B87067446856884344936</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/00CEA8C9D1AA8C904F6B87067446856884344936/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/00CEA8C9D1AA8C904F6B87067446856884344936/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/00CEA8C9D1AA8C904F6B87067446856884344936/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Dopamine D2 receptor knockout mice develop features of Parkinson disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2009</date></publicationStmt><notesStmt><note type="content">*Potential conflict of interest: Nothing to report.</note><note>National Health and Medical Research Council (NHMRC) of Australia</note><note>NHMRC CJ Martin Fellowship</note><note>Brain Foundations</note><note>Bethlehem Griffiths Research Foundation</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Dopamine D2 receptor knockout mice develop features of Parkinson disease</title><author><persName><forename type="first">Rogan B.</forename><surname>Tinsley</surname></persName><roleName type="degree">PhD</roleName><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Chris R.</forename><surname>Bye</surname></persName><roleName type="degree">BSc (Hon)</roleName><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Clare L.</forename><surname>Parish</surname></persName><roleName type="degree">PhD</roleName><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Angela</forename><surname>Tziotis‐Vais</surname></persName><roleName type="degree">BSc (Hon)</roleName><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Sonia</forename><surname>George</surname></persName><roleName type="degree">PhD</roleName><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Janetta G.</forename><surname>Culvenor</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Qiao‐Xin</forename><surname>Li</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Colin L.</forename><surname>Masters</surname></persName><roleName type="degree">MD</roleName><affiliation>Mental Health Research Institute, Parkville, Australia</affiliation></author><author><persName><forename type="first">David I.</forename><surname>Finkelstein</surname></persName><roleName type="degree">PhD</roleName><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation></author><author><persName><forename type="first">Malcolm K.</forename><surname>Horne</surname></persName><roleName type="degree">MD, PhD</roleName><note type="correspondence"><p>Correspondence: Howard Florey Institute, University of Melbourne, VIC 3010, Parkville, Australia</p></note><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Department of Neurology, St Vincent's Hospital, Fitzroy, Australia</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-10"></date><biblScope unit="volume">66</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="472">472</biblScope><biblScope unit="page" to="484">484</biblScope></imprint></monogr><idno type="istex">00CEA8C9D1AA8C904F6B87067446856884344936</idno><idno type="DOI">10.1002/ana.21716</idno><idno type="ArticleID">ANA21716</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Objective: This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α‐synuclein–containing cytoplasmic inclusion of Parkinson disease (PD). Methods: Mice with targeted deletion of the dopamine D2 receptor gene (D2R[−/−]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy. Results: LB‐like cytoplasmic inclusions containing α‐synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D2R(−/−) mice, and were also occasionally seen in aged wild‐type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic α‐synuclein immunoreactivity in SNpc neurons increased with age in both wild‐type and D2R(−/−) mice, most likely because of redistribution of α‐synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D2R(−/−) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc. Interpretation: Increased sprouting and DA turnover, as observed in PD and D2R(−/−) mice, augments LB‐like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy. Ann Neurol 2009;66:472–484</p></abstract><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Original Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2007-12-07">Received</change><change when="2009-03-20">Registration</change><change when="2009-10">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/00CEA8C9D1AA8C904F6B87067446856884344936/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)1531-8249</doi><issn type="print">0364-5134</issn><issn type="electronic">1531-8249</issn><idGroup><id type="product" value="ANA"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="ANNALS OF NEUROLOGY">Annals of Neurology</title><title type="short">Ann Neurol.</title></titleGroup></publicationMeta><publicationMeta level="part" position="40"><doi origin="wiley" registered="yes">10.1002/ana.v66:4</doi><numberingGroup><numbering type="journalVolume" number="66">66</numbering><numbering type="journalIssue">4</numbering></numberingGroup><coverDate startDate="2009-10">October 2009</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="100" status="forIssue"><doi origin="wiley" registered="yes">10.1002/ana.21716</doi><idGroup><id type="unit" value="ANA21716"></id></idGroup><countGroup><count type="pageTotal" number="13"></count></countGroup><titleGroup><title type="articleCategory">Original Article</title><title type="tocHeading1">Original Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2009 American Neurological Association</copyright><eventGroup><event type="manuscriptReceived" date="2007-12-07"></event><event type="manuscriptRevised" date="2009-02-16"></event><event type="manuscriptAccepted" date="2009-03-20"></event><event type="firstOnline" date="2009-03-26"></event><event type="publishedOnlineFinalForm" date="2009-10-08"></event><event type="publishedOnlineAcceptedOrEarlyUnpaginated" date="2009-03-26"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.4.7 mode:FullText source:FullText result:FullText" date="2011-02-24"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-03"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst">472</numbering><numbering type="pageLast">484</numbering></numberingGroup><correspondenceTo>Howard Florey Institute, University of Melbourne, VIC 3010, Parkville, Australia</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:ANA.ANA21716.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="5"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="79"></count><count type="wordTotal" number="8554"></count></countGroup><titleGroup><title type="main" xml:lang="en">Dopamine D<sup>2</sup> receptor knockout mice develop features of Parkinson disease<link href="#fn1"></link></title><title type="short" xml:lang="en">D<sub>2</sub>R(−/−) Mice and PD Pathology</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Rogan B.</givenNames><familyName>Tinsley</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Chris R.</givenNames><familyName>Bye</familyName><degrees>BSc (Hon)</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Clare L.</givenNames><familyName>Parish</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Angela</givenNames><familyName>Tziotis‐Vais</familyName><degrees>BSc (Hon)</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1 #af2 #af3"><personName><givenNames>Sonia</givenNames><familyName>George</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Janetta G.</givenNames><familyName>Culvenor</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Qiao‐Xin</givenNames><familyName>Li</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Colin L.</givenNames><familyName>Masters</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af3"><personName><givenNames>David I.</givenNames><familyName>Finkelstein</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af1 #af3 #af5" corresponding="yes"><personName><givenNames>Malcolm K.</givenNames><familyName>Horne</familyName><degrees>MD, PhD</degrees></personName><contactDetails><email>m.horne@florey.edu.au</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="AU" type="organization"><unparsedAffiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="AU" type="organization"><unparsedAffiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="AU" type="organization"><unparsedAffiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="AU" type="organization"><unparsedAffiliation>Mental Health Research Institute, Parkville, Australia</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="AU" type="organization"><unparsedAffiliation>Department of Neurology, St Vincent's Hospital, Fitzroy, Australia</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>National Health and Medical Research Council (NHMRC) of Australia</fundingAgency></fundingInfo><fundingInfo><fundingAgency>NHMRC CJ Martin Fellowship</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Brain Foundations</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Bethlehem Griffiths Research Foundation</fundingAgency></fundingInfo><supportingInformation><p> Additional Supporting Information may be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21716:ANA_21716_sm_SupFig1"></mediaResource><caption>Supplementary Figure 1.</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><section xml:id="abs1-1"><title type="main">Objective</title><p>This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α‐synuclein–containing cytoplasmic inclusion of Parkinson disease (PD).</p></section><section xml:id="abs1-2"><title type="main">Methods</title><p>Mice with targeted deletion of the dopamine D<sub>2</sub> receptor gene (D<sub>2</sub>R[−/−]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy.</p></section><section xml:id="abs1-3"><title type="main">Results</title><p>LB‐like cytoplasmic inclusions containing α‐synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D<sub>2</sub>R(−/−) mice, and were also occasionally seen in aged wild‐type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic α‐synuclein immunoreactivity in SNpc neurons increased with age in both wild‐type and D<sub>2</sub>R(−/−) mice, most likely because of redistribution of α‐synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D<sub>2</sub>R(−/−) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc.</p></section><section xml:id="abs1-4"><title type="main">Interpretation</title><p>Increased sprouting and DA turnover, as observed in PD and D<sub>2</sub>R(−/−) mice, augments LB‐like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy. Ann Neurol 2009;66:472–484</p></section></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Potential conflict of interest: Nothing to report.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Dopamine D2 receptor knockout mice develop features of Parkinson disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>D2R(−/−) Mice and PD Pathology</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Dopamine D</title></titleInfo><name type="personal"><namePart type="given">Rogan B.</namePart><namePart type="family">Tinsley</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chris R.</namePart><namePart type="family">Bye</namePart><namePart type="termsOfAddress">BSc (Hon)</namePart><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Clare L.</namePart><namePart type="family">Parish</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Angela</namePart><namePart type="family">Tziotis‐Vais</namePart><namePart type="termsOfAddress">BSc (Hon)</namePart><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sonia</namePart><namePart type="family">George</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Janetta G.</namePart><namePart type="family">Culvenor</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Qiao‐Xin</namePart><namePart type="family">Li</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Pathology, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Colin L.</namePart><namePart type="family">Masters</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Mental Health Research Institute, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David I.</namePart><namePart type="family">Finkelstein</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Malcolm K.</namePart><namePart type="family">Horne</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Neural Injury and Repair Group, Howard Florey Institute, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Centre for Neuroscience, the University of Melbourne, Parkville, Australia</affiliation><affiliation>Department of Neurology, St Vincent's Hospital, Fitzroy, Australia</affiliation><description>Correspondence: Howard Florey Institute, University of Melbourne, VIC 3010, Parkville, Australia</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">2009-10</dateIssued><dateCaptured encoding="w3cdtf">2007-12-07</dateCaptured><dateValid encoding="w3cdtf">2009-03-20</dateValid><copyrightDate encoding="w3cdtf">2009</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">5</extent><extent unit="references">79</extent><extent unit="words">8554</extent></physicalDescription><abstract lang="en">Objective: This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α‐synuclein–containing cytoplasmic inclusion of Parkinson disease (PD). Methods: Mice with targeted deletion of the dopamine D2 receptor gene (D2R[−/−]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy. Results: LB‐like cytoplasmic inclusions containing α‐synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D2R(−/−) mice, and were also occasionally seen in aged wild‐type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic α‐synuclein immunoreactivity in SNpc neurons increased with age in both wild‐type and D2R(−/−) mice, most likely because of redistribution of α‐synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D2R(−/−) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc. Interpretation: Increased sprouting and DA turnover, as observed in PD and D2R(−/−) mice, augments LB‐like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy. Ann Neurol 2009;66:472–484</abstract><note type="content">*Potential conflict of interest: Nothing to report.</note><note type="funding">National Health and Medical Research Council (NHMRC) of Australia</note><note type="funding">NHMRC CJ Martin Fellowship</note><note type="funding">Brain Foundations</note><note type="funding">Bethlehem Griffiths Research Foundation</note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: Supplementary Figure 1. - </note><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>66</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>472</start><end>484</end><total>13</total></extent></part></relatedItem><identifier type="istex">00CEA8C9D1AA8C904F6B87067446856884344936</identifier><identifier type="DOI">10.1002/ana.21716</identifier><identifier type="ArticleID">ANA21716</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2009 American Neurological Association</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)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002E39 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Corpus/biblio.hfd -nk 002E39 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonV1
|flux= Main
|étape= Corpus
|type= RBID
|clé= ISTEX:00CEA8C9D1AA8C904F6B87067446856884344936
|texte= Dopamine D2 receptor knockout mice develop features of Parkinson disease
}}
| This area was generated with Dilib version V0.6.23. |  |