Progressive sensorimotor impairment is not associated with reduced dopamine and high energy phosphate donors in a model of ataxia-telangiectasia
Identifieur interne : 000270 ( France/Analysis ); précédent : 000269; suivant : 000271Progressive sensorimotor impairment is not associated with reduced dopamine and high energy phosphate donors in a model of ataxia-telangiectasia
Auteurs : Howard T. J. Mount [Canada] ; Jean-Claude Martel [France] ; Paul Fluit [Canada] ; YINGJI WU [Canada] ; Eleanor Gallo-Hendrikx [Canada] ; Cristina Cosi [France] ; Marc R. Marien [France]Source :
- Journal of neurochemistry [ 0022-3042 ] ; 2004.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
Ataxia-telangiectasia (A-T) is a genetic disease, associated with progressive motor impairment and a lack of functional ATM protein. It has been reported that immunoreactive tyrosine hydroxylase and dopamine transporter are reduced in an Atm-/- mouse model of A-T. These observations led to a hypothesis that A-T is associated with loss of nigrostriatal dopamine and prompted the launch of clinical trials to evaluate a therapeutic utility of the anti-parkinsonian drug, L-DOPA. To test for dopamine depletion more directly, we measured regional levels of monoamines and their metabolites in the Atm-/-mouse brain. We also measured levels of NAD+, a cofactor for dopamine biosynthesis and substrate of the DNA damage surveillance enzyme, poly(ADP-ribose) polymerase (PARP). Constitutive activation of PARP has been posited to cause NAD+ depletion. We observed no reduction in monoamine transmitters and no depletion of NAD+, or other high energy phosphate donors in the adult Atm-/- cerebellum, striatum, or ventral mesencephalon. However, our studies did reveal a progressive sensorimotor impairment in Atm-/-mice that may serve as a relevant proxy for progressive neurological impairment in the human disease. Our results call into question the involvement of dopamine in A-T and the therapeutic strategy of enhancing dopaminergic function with L-DOPA.
Affiliations:
- Canada, France
- Midi-Pyrénées, Occitanie (région administrative), Ontario
- Castres, Toronto
- Université de Toronto
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Pascal:04-0345628Le document en format XML
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J." last="Mount">Howard T. J. Mount</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Division of Neurology, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Martel, Jean Claude" sort="Martel, Jean Claude" uniqKey="Martel J" first="Jean-Claude" last="Martel">Jean-Claude Martel</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Institut de Reclterche Pierre Fabre</s1><s2>Castres</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Castres</settlement></placeName></affiliation></author><author><name sortKey="Fluit, Paul" sort="Fluit, Paul" uniqKey="Fluit P" first="Paul" last="Fluit">Paul Fluit</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Yingji Wu" sort="Yingji Wu" uniqKey="Yingji Wu" last="Yingji Wu">YINGJI WU</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Gallo Hendrikx, Eleanor" sort="Gallo Hendrikx, Eleanor" uniqKey="Gallo Hendrikx E" first="Eleanor" last="Gallo-Hendrikx">Eleanor Gallo-Hendrikx</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Cosi, Cristina" sort="Cosi, Cristina" uniqKey="Cosi C" first="Cristina" last="Cosi">Cristina Cosi</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Institut de Reclterche Pierre Fabre</s1><s2>Castres</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Castres</settlement></placeName></affiliation></author><author><name sortKey="Marien, Marc R" sort="Marien, Marc R" uniqKey="Marien M" first="Marc R." last="Marien">Marc R. Marien</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Institut de Reclterche Pierre Fabre</s1><s2>Castres</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Castres</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">Journal of neurochemistry</title><title level="j" type="abbreviated">J. neurochem.</title><idno type="ISSN">0022-3042</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of neurochemistry</title><title level="j" type="abbreviated">J. neurochem.</title><idno type="ISSN">0022-3042</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal</term><term>Ataxia telangiectasia</term><term>Biosynthesis</term><term>Cerebellum</term><term>Depletion</term><term>Dopamine</term><term>Mouse</term><term>Nigrostriatal pathway</term><term>Parkinson disease</term><term>Posture</term><term>Sensorimotor coordination</term><term>Tyrosine 3-monooxygenase</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Dopamine</term><term>Déplétion</term><term>Biosynthèse</term><term>Voie nigrostriatale</term><term>Tyrosine 3-monooxygenase</term><term>Coordination sensorimotrice</term><term>Ataxie télangiectasie</term><term>Posture</term><term>Cervelet</term><term>Parkinson maladie</term><term>Souris</term><term>Animal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Ataxia-telangiectasia (A-T) is a genetic disease, associated with progressive motor impairment and a lack of functional ATM protein. It has been reported that immunoreactive tyrosine hydroxylase and dopamine transporter are reduced in an Atm<sup>-/-</sup> mouse model of A-T. These observations led to a hypothesis that A-T is associated with loss of nigrostriatal dopamine and prompted the launch of clinical trials to evaluate a therapeutic utility of the anti-parkinsonian drug, L-DOPA. To test for dopamine depletion more directly, we measured regional levels of monoamines and their metabolites in the Atm<sup>-/-</sup>mouse brain. We also measured levels of NAD<sup>+</sup>, a cofactor for dopamine biosynthesis and substrate of the DNA damage surveillance enzyme, poly(ADP-ribose) polymerase (PARP). Constitutive activation of PARP has been posited to cause NAD<sup>+</sup> depletion. We observed no reduction in monoamine transmitters and no depletion of NAD<sup>+</sup>, or other high energy phosphate donors in the adult Atm<sup>-/-</sup> cerebellum, striatum, or ventral mesencephalon. However, our studies did reveal a progressive sensorimotor impairment in Atm<sup>-/-</sup>mice that may serve as a relevant proxy for progressive neurological impairment in the human disease. Our results call into question the involvement of dopamine in A-T and the therapeutic strategy of enhancing dopaminergic function with L-DOPA.</div></front></TEI><affiliations><list><country><li>Canada</li><li>France</li></country><region><li>Midi-Pyrénées</li><li>Occitanie (région administrative)</li><li>Ontario</li></region><settlement><li>Castres</li><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><region name="Ontario"><name sortKey="Mount, Howard T J" sort="Mount, Howard T J" uniqKey="Mount H" first="Howard T. J." last="Mount">Howard T. J. Mount</name></region><name sortKey="Fluit, Paul" sort="Fluit, Paul" uniqKey="Fluit P" first="Paul" last="Fluit">Paul Fluit</name><name sortKey="Gallo Hendrikx, Eleanor" sort="Gallo Hendrikx, Eleanor" uniqKey="Gallo Hendrikx E" first="Eleanor" last="Gallo-Hendrikx">Eleanor Gallo-Hendrikx</name><name sortKey="Mount, Howard T J" sort="Mount, Howard T J" uniqKey="Mount H" first="Howard T. J." last="Mount">Howard T. J. Mount</name><name sortKey="Yingji Wu" sort="Yingji Wu" uniqKey="Yingji Wu" last="Yingji Wu">YINGJI WU</name></country><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Martel, Jean Claude" sort="Martel, Jean Claude" uniqKey="Martel J" first="Jean-Claude" last="Martel">Jean-Claude Martel</name></region><name sortKey="Cosi, Cristina" sort="Cosi, Cristina" uniqKey="Cosi C" first="Cristina" last="Cosi">Cristina Cosi</name><name sortKey="Marien, Marc R" sort="Marien, Marc R" uniqKey="Marien M" first="Marc R." last="Marien">Marc R. Marien</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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