Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse
Identifieur interne : 001E85 ( Main/Corpus ); précédent : 001E84; suivant : 001E86Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse
Auteurs : Jean-Michel Itier ; Pablo Iba N Ez ; Mari A Angeles Mena ; Nacer Abbas ; Charles Cohen-Salmon ; Georg Andrees Bohme ; Michel Laville ; Jeremy Pratt ; Olga Corti ; Laurent Pradier ; Gwe Na Elle Ret ; Chantal Joubert ; Magali Periquet ; Francisco Araujo ; Julia Negroni ; Mari A Jose Casarejos ; Santiago Canals ; Rosa Solano ; Alba Serrano ; Eva Gallego ; Marina Sa Nchez ; Patrice Dene Fle ; Jesu S Benavides ; Gu Nter Tremp ; Thomas A. Rooney ; Alexis Brice ; Justo Garci A De Ye BenesSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2003-09-15.
Abstract
Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.
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DOI: 10.1093/hmg/ddg239
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse</title><author><name sortKey="Itier, Jean Michel" sort="Itier, Jean Michel" uniqKey="Itier J" first="Jean-Michel" last="Itier">Jean-Michel Itier</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Iba N Ez, Pablo" sort="Iba N Ez, Pablo" uniqKey="Iba N Ez P" first="Pablo" last="Iba N Ez">Pablo Iba N Ez</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Mena, Mari A Angeles" sort="Mena, Mari A Angeles" uniqKey="Mena M" first="Mari A Angeles" last="Mena">Mari A Angeles 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Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Laville, Michel" sort="Laville, Michel" uniqKey="Laville M" first="Michel" last="Laville">Michel Laville</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Pratt, Jeremy" sort="Pratt, Jeremy" uniqKey="Pratt J" first="Jeremy" last="Pratt">Jeremy Pratt</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Pradier, Laurent" sort="Pradier, Laurent" uniqKey="Pradier L" first="Laurent" last="Pradier">Laurent Pradier</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Ret, Gwe Na Elle" sort="Ret, Gwe Na Elle" uniqKey="Ret G" first="Gwe Na Elle" last="Ret">Gwe Na Elle Ret</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Joubert, Chantal" sort="Joubert, Chantal" uniqKey="Joubert C" first="Chantal" last="Joubert">Chantal Joubert</name><affiliation><mods:affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Periquet, Magali" sort="Periquet, Magali" uniqKey="Periquet M" first="Magali" last="Periquet">Magali Periquet</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Araujo, Francisco" sort="Araujo, Francisco" uniqKey="Araujo F" first="Francisco" last="Araujo">Francisco Araujo</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Negroni, Julia" sort="Negroni, Julia" uniqKey="Negroni J" first="Julia" last="Negroni">Julia Negroni</name><affiliation><mods:affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Casarejos, Mari A Jose" sort="Casarejos, Mari A Jose" uniqKey="Casarejos M" first="Mari A Jose" last="Casarejos">Mari A Jose Casarejos</name><affiliation><mods:affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</mods:affiliation></affiliation></author><author><name sortKey="Canals, Santiago" sort="Canals, Santiago" uniqKey="Canals S" first="Santiago" last="Canals">Santiago Canals</name><affiliation><mods:affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</mods:affiliation></affiliation></author><author><name sortKey="Solano, Rosa" sort="Solano, Rosa" uniqKey="Solano R" first="Rosa" last="Solano">Rosa Solano</name><affiliation><mods:affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</mods:affiliation></affiliation></author><author><name sortKey="Serrano, Alba" sort="Serrano, Alba" uniqKey="Serrano A" first="Alba" last="Serrano">Alba Serrano</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author><author><name sortKey="Gallego, Eva" sort="Gallego, Eva" uniqKey="Gallego E" first="Eva" last="Gallego">Eva Gallego</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author><author><name sortKey="Sa Nchez, Marina" sort="Sa Nchez, Marina" uniqKey="Sa Nchez M" first="Marina" last="Sa Nchez">Marina Sa Nchez</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author><author><name sortKey="Dene Fle, Patrice" sort="Dene Fle, Patrice" uniqKey="Dene Fle P" first="Patrice" last="Dene Fle">Patrice Dene Fle</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Benavides, Jesu S" sort="Benavides, Jesu S" uniqKey="Benavides J" first="Jesu S" last="Benavides">Jesu S Benavides</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Tremp, Gu Nter" sort="Tremp, Gu Nter" uniqKey="Tremp G" first="Gu Nter" last="Tremp">Gu Nter Tremp</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Rooney, Thomas A" sort="Rooney, Thomas A" uniqKey="Rooney T" first="Thomas A." last="Rooney">Thomas A. Rooney</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>Département de Génétique, Cytogénétique et Embryologie, Groupe Hopitalier Pitié-Salpêtrière, AP-HP, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France</mods:affiliation></affiliation></author><author><name sortKey="Garci A De Ye Benes, Justo" sort="Garci A De Ye Benes, Justo" uniqKey="Garci A De Ye Benes J" first="Justo" last="Garci A De Ye Benes">Justo Garci A De Ye Benes</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:CF16ADEC7627F46229CE703E26898F55B09AFF14</idno><date when="2003" year="2003">2003</date><idno type="doi">10.1093/hmg/ddg239</idno><idno type="url">https://api.istex.fr/document/CF16ADEC7627F46229CE703E26898F55B09AFF14/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001E85</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse</title><author><name sortKey="Itier, Jean Michel" sort="Itier, Jean Michel" uniqKey="Itier J" first="Jean-Michel" last="Itier">Jean-Michel Itier</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Iba N Ez, Pablo" sort="Iba N Ez, Pablo" uniqKey="Iba N Ez P" first="Pablo" last="Iba N Ez">Pablo Iba N Ez</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Mena, Mari A Angeles" sort="Mena, Mari A Angeles" uniqKey="Mena M" first="Mari A Angeles" last="Mena">Mari A Angeles Mena</name><affiliation><mods:affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</mods:affiliation></affiliation></author><author><name sortKey="Abbas, Nacer" sort="Abbas, Nacer" uniqKey="Abbas N" first="Nacer" last="Abbas">Nacer Abbas</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Cohen Salmon, Charles" sort="Cohen Salmon, Charles" uniqKey="Cohen Salmon C" first="Charles" last="Cohen-Salmon">Charles Cohen-Salmon</name><affiliation><mods:affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Bohme, Georg Andrees" sort="Bohme, Georg Andrees" uniqKey="Bohme G" first="Georg Andrees" last="Bohme">Georg Andrees Bohme</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Laville, Michel" sort="Laville, Michel" uniqKey="Laville M" first="Michel" last="Laville">Michel Laville</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Pratt, Jeremy" sort="Pratt, Jeremy" uniqKey="Pratt J" first="Jeremy" last="Pratt">Jeremy Pratt</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Pradier, Laurent" sort="Pradier, Laurent" uniqKey="Pradier L" first="Laurent" last="Pradier">Laurent Pradier</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Ret, Gwe Na Elle" sort="Ret, Gwe Na Elle" uniqKey="Ret G" first="Gwe Na Elle" last="Ret">Gwe Na Elle Ret</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Joubert, Chantal" sort="Joubert, Chantal" uniqKey="Joubert C" first="Chantal" last="Joubert">Chantal Joubert</name><affiliation><mods:affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Periquet, Magali" sort="Periquet, Magali" uniqKey="Periquet M" first="Magali" last="Periquet">Magali Periquet</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Araujo, Francisco" sort="Araujo, Francisco" uniqKey="Araujo F" first="Francisco" last="Araujo">Francisco Araujo</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Negroni, Julia" sort="Negroni, Julia" uniqKey="Negroni J" first="Julia" last="Negroni">Julia Negroni</name><affiliation><mods:affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation></author><author><name sortKey="Casarejos, Mari A Jose" sort="Casarejos, Mari A Jose" uniqKey="Casarejos M" first="Mari A Jose" last="Casarejos">Mari A Jose Casarejos</name><affiliation><mods:affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</mods:affiliation></affiliation></author><author><name sortKey="Canals, Santiago" sort="Canals, Santiago" uniqKey="Canals S" first="Santiago" last="Canals">Santiago Canals</name><affiliation><mods:affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</mods:affiliation></affiliation></author><author><name sortKey="Solano, Rosa" sort="Solano, Rosa" uniqKey="Solano R" first="Rosa" last="Solano">Rosa Solano</name><affiliation><mods:affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</mods:affiliation></affiliation></author><author><name sortKey="Serrano, Alba" sort="Serrano, Alba" uniqKey="Serrano A" first="Alba" last="Serrano">Alba Serrano</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author><author><name sortKey="Gallego, Eva" sort="Gallego, Eva" uniqKey="Gallego E" first="Eva" last="Gallego">Eva Gallego</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author><author><name sortKey="Sa Nchez, Marina" sort="Sa Nchez, Marina" uniqKey="Sa Nchez M" first="Marina" last="Sa Nchez">Marina Sa Nchez</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author><author><name sortKey="Dene Fle, Patrice" sort="Dene Fle, Patrice" uniqKey="Dene Fle P" first="Patrice" last="Dene Fle">Patrice Dene Fle</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Benavides, Jesu S" sort="Benavides, Jesu S" uniqKey="Benavides J" first="Jesu S" last="Benavides">Jesu S Benavides</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Tremp, Gu Nter" sort="Tremp, Gu Nter" uniqKey="Tremp G" first="Gu Nter" last="Tremp">Gu Nter Tremp</name><affiliation><mods:affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Rooney, Thomas A" sort="Rooney, Thomas A" uniqKey="Rooney T" first="Thomas A." last="Rooney">Thomas A. Rooney</name><affiliation><mods:affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</mods:affiliation></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><mods:affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>Département de Génétique, Cytogénétique et Embryologie, Groupe Hopitalier Pitié-Salpêtrière, AP-HP, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France</mods:affiliation></affiliation></author><author><name sortKey="Garci A De Ye Benes, Justo" sort="Garci A De Ye Benes, Justo" uniqKey="Garci A De Ye Benes J" first="Justo" last="Garci A De Ye Benes">Justo Garci A De Ye Benes</name><affiliation><mods:affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2003-09-15">2003-09-15</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">18</biblScope><biblScope unit="page" from="2277">2277</biblScope><biblScope unit="page" to="2291">2291</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">CF16ADEC7627F46229CE703E26898F55B09AFF14</idno><idno type="DOI">10.1093/hmg/ddg239</idno><idno type="local">ddg239</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Jean-Michel Itier</name><affiliations><json:string>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Pablo Ibáñez</name><affiliations><json:string>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string></affiliations></json:item><json:item><name>María Angeles Mena</name><affiliations><json:string>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</json:string></affiliations></json:item><json:item><name>Nacer Abbas</name><affiliations><json:string>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string></affiliations></json:item><json:item><name>Charles Cohen-Salmon</name><affiliations><json:string>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string></affiliations></json:item><json:item><name>Georg Andrees Bohme</name><affiliations><json:string>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Michel Laville</name><affiliations><json:string>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Jeremy Pratt</name><affiliations><json:string>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Olga Corti</name><affiliations><json:string>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string></affiliations></json:item><json:item><name>Laurent Pradier</name><affiliations><json:string>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Gwénäelle Ret</name><affiliations><json:string>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Chantal Joubert</name><affiliations><json:string>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string></affiliations></json:item><json:item><name>Magali Periquet</name><affiliations><json:string>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string></affiliations></json:item><json:item><name>Francisco Araujo</name><affiliations><json:string>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Julia Negroni</name><affiliations><json:string>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string></affiliations></json:item><json:item><name>María José Casarejos</name><affiliations><json:string>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</json:string></affiliations></json:item><json:item><name>Santiago Canals</name><affiliations><json:string>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</json:string></affiliations></json:item><json:item><name>Rosa Solano</name><affiliations><json:string>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</json:string></affiliations></json:item><json:item><name>Alba Serrano</name><affiliations><json:string>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</json:string></affiliations></json:item><json:item><name>Eva Gallego</name><affiliations><json:string>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</json:string></affiliations></json:item><json:item><name>Marina Sánchez</name><affiliations><json:string>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</json:string></affiliations></json:item><json:item><name>Patrice Denèfle</name><affiliations><json:string>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Jesús Benavides</name><affiliations><json:string>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Günter Tremp</name><affiliations><json:string>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Thomas A. Rooney</name><affiliations><json:string>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</json:string></affiliations></json:item><json:item><name>Alexis Brice</name><affiliations><json:string>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</json:string><json:string>Département de Génétique, Cytogénétique et Embryologie, Groupe Hopitalier Pitié-Salpêtrière, AP-HP, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France</json:string></affiliations></json:item><json:item><name>Justo García de Yébenes</name><affiliations><json:string>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Article</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.</abstract><qualityIndicators><score>7.148</score><pdfVersion>1.2</pdfVersion><pdfPageSize>609.675 x 795.005 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1211</abstractCharCount><pdfWordCount>10910</pdfWordCount><pdfCharCount>67460</pdfCharCount><pdfPageCount>15</pdfPageCount><abstractWordCount>179</abstractWordCount></qualityIndicators><title>Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse</title><genre><json:string>research-article</json:string></genre><host><volume>12</volume><pages><last>2291</last><first>2277</first></pages><issn><json:string>0964-6906</json:string></issn><issue>18</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular Genetics</title></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>GENETICS & HEREDITY</json:string></wos></categories><publicationDate>2003</publicationDate><copyrightDate>2003</copyrightDate><doi><json:string>10.1093/hmg/ddg239</json:string></doi><id>CF16ADEC7627F46229CE703E26898F55B09AFF14</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/CF16ADEC7627F46229CE703E26898F55B09AFF14/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/CF16ADEC7627F46229CE703E26898F55B09AFF14/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/CF16ADEC7627F46229CE703E26898F55B09AFF14/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse</title><respStmt xml:id="ISTEX-API" resp="Références bibliographiques récupérées via 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of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation></author><author><persName><forename type="first">Nacer</forename><surname>Abbas</surname></persName><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation></author><author><persName><forename type="first">Charles</forename><surname>Cohen-Salmon</surname></persName><affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation></author><author><persName><forename type="first">Georg Andrees</forename><surname>Bohme</surname></persName><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Michel</forename><surname>Laville</surname></persName><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Jeremy</forename><surname>Pratt</surname></persName><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Olga</forename><surname>Corti</surname></persName><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation></author><author><persName><forename type="first">Laurent</forename><surname>Pradier</surname></persName><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Gwénäelle</forename><surname>Ret</surname></persName><affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Chantal</forename><surname>Joubert</surname></persName><affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation></author><author><persName><forename type="first">Magali</forename><surname>Periquet</surname></persName><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation></author><author><persName><forename type="first">Francisco</forename><surname>Araujo</surname></persName><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Julia</forename><surname>Negroni</surname></persName><affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation></author><author><persName><forename type="first">María José</forename><surname>Casarejos</surname></persName><affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation></author><author><persName><forename type="first">Santiago</forename><surname>Canals</surname></persName><affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation></author><author><persName><forename type="first">Rosa</forename><surname>Solano</surname></persName><affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation></author><author><persName><forename type="first">Alba</forename><surname>Serrano</surname></persName><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation></author><author><persName><forename type="first">Eva</forename><surname>Gallego</surname></persName><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation></author><author><persName><forename type="first">Marina</forename><surname>Sánchez</surname></persName><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation></author><author><persName><forename type="first">Patrice</forename><surname>Denèfle</surname></persName><affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Jesús</forename><surname>Benavides</surname></persName><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Günter</forename><surname>Tremp</surname></persName><affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Thomas A.</forename><surname>Rooney</surname></persName><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation></author><author><persName><forename type="first">Alexis</forename><surname>Brice</surname></persName><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><affiliation>Département de Génétique, Cytogénétique et Embryologie, Groupe Hopitalier Pitié-Salpêtrière, AP-HP, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France</affiliation></author><author><persName><forename type="first">Justo</forename><surname>García de Yébenes</surname></persName><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2003-09-15"></date><biblScope unit="volume">12</biblScope><biblScope unit="issue">18</biblScope><biblScope unit="page" from="2277">2277</biblScope><biblScope unit="page" to="2291">2291</biblScope></imprint></monogr><idno type="istex">CF16ADEC7627F46229CE703E26898F55B09AFF14</idno><idno type="DOI">10.1093/hmg/ddg239</idno><idno type="local">ddg239</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2003</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.</p></abstract></profileDesc><revisionDesc><change when="2003-09-15">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/CF16ADEC7627F46229CE703E26898F55B09AFF14/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">Hum. Mol. Genet.</abbrev-journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">ddg239</article-id><article-id pub-id-type="doi">10.1093/hmg/ddg239</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Itier</surname><given-names>Jean-Michel</given-names></name><xref rid="AF1">1</xref><xref rid="FN2">†</xref></contrib><contrib contrib-type="author"><name><surname>Ibáñez</surname><given-names>Pablo</given-names></name><xref rid="AF2">2</xref><xref rid="FN2">†</xref></contrib><contrib contrib-type="author"><name><surname>Mena</surname><given-names>María Angeles</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Abbas</surname><given-names>Nacer</given-names></name><xref rid="AF2">2</xref><xref rid="FN3">‡</xref></contrib><contrib contrib-type="author"><name><surname>Cohen-Salmon</surname><given-names>Charles</given-names></name><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Bohme</surname><given-names>Georg Andrees</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Laville</surname><given-names>Michel</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Pratt</surname><given-names>Jeremy</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Corti</surname><given-names>Olga</given-names></name><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Pradier</surname><given-names>Laurent</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Ret</surname><given-names>Gwénäelle</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Joubert</surname><given-names>Chantal</given-names></name><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Periquet</surname><given-names>Magali</given-names></name><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Araujo</surname><given-names>Francisco</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Negroni</surname><given-names>Julia</given-names></name><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Casarejos</surname><given-names>María José</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Canals</surname><given-names>Santiago</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Solano</surname><given-names>Rosa</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Serrano</surname><given-names>Alba</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gallego</surname><given-names>Eva</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Sánchez</surname><given-names>Marina</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Denèfle</surname><given-names>Patrice</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Benavides</surname><given-names>Jesús</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Tremp</surname><given-names>Günter</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rooney</surname><given-names>Thomas A.</given-names></name><xref rid="AF5">5</xref><xref rid="FN1">*</xref></contrib><contrib contrib-type="author"><name><surname>Brice</surname><given-names>Alexis</given-names></name><xref rid="AF2">2</xref><xref rid="AF7">7</xref></contrib><contrib contrib-type="author"><name><surname>García de Yébenes</surname><given-names>Justo</given-names></name><xref rid="AF6">6</xref></contrib><aff id="AF1"><sup>1</sup>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</aff><aff id="AF2"><sup>2</sup>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</aff><aff id="AF3"><sup>3</sup>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</aff><aff id="AF4"><sup>4</sup>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</aff><aff id="AF5"><sup>5</sup>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</aff><aff id="AF6"><sup>6</sup>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</aff><aff id="AF7"><sup>7</sup>Département de Génétique, Cytogénétique et Embryologie, Groupe Hopitalier Pitié-Salpêtrière, AP-HP, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France</aff></contrib-group><pub-date pub-type="ppub"><day>15</day><month>09</month><year>2003</year></pub-date><volume>12</volume><issue>18</issue><fpage>2277</fpage><lpage>2291</lpage><history><date date-type="accepted"><day>10</day><month>07</month><year>2003</year></date><date date-type="received"><day>10</day><month>04</month><year>2003</year></date><date date-type="rev-recd"><day>13</day><month>06</month><year>2003</year></date></history><permissions><copyright-year>2003</copyright-year></permissions><abstract xml:lang="en"><p>Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>2277</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse</title></titleInfo><name type="personal"><namePart type="given">Jean-Michel</namePart><namePart type="family">Itier</namePart><affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Pablo</namePart><namePart type="family">Ibáñez</namePart><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">María Angeles</namePart><namePart type="family">Mena</namePart><affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nacer</namePart><namePart type="family">Abbas</namePart><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Charles</namePart><namePart type="family">Cohen-Salmon</namePart><affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Georg Andrees</namePart><namePart type="family">Bohme</namePart><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michel</namePart><namePart type="family">Laville</namePart><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeremy</namePart><namePart type="family">Pratt</namePart><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Olga</namePart><namePart type="family">Corti</namePart><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laurent</namePart><namePart type="family">Pradier</namePart><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gwénäelle</namePart><namePart type="family">Ret</namePart><affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chantal</namePart><namePart type="family">Joubert</namePart><affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Magali</namePart><namePart type="family">Periquet</namePart><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Francisco</namePart><namePart type="family">Araujo</namePart><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Julia</namePart><namePart type="family">Negroni</namePart><affiliation>CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">María José</namePart><namePart type="family">Casarejos</namePart><affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Santiago</namePart><namePart type="family">Canals</namePart><affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rosa</namePart><namePart type="family">Solano</namePart><affiliation>Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alba</namePart><namePart type="family">Serrano</namePart><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eva</namePart><namePart type="family">Gallego</namePart><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marina</namePart><namePart type="family">Sánchez</namePart><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrice</namePart><namePart type="family">Denèfle</namePart><affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jesús</namePart><namePart type="family">Benavides</namePart><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Günter</namePart><namePart type="family">Tremp</namePart><affiliation>Functional Genomics Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas A.</namePart><namePart type="family">Rooney</namePart><affiliation>CNS Department, Aventis Pharma SA, 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexis</namePart><namePart type="family">Brice</namePart><affiliation>INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France,</affiliation><affiliation>Département de Génétique, Cytogénétique et Embryologie, Groupe Hopitalier Pitié-Salpêtrière, AP-HP, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Justo</namePart><namePart type="family">García de Yébenes</namePart><affiliation>Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 Madrid, Spain and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2003-09-15</dateIssued><copyrightDate encoding="w3cdtf">2003</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. 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