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Progressive sensorimotor impairment is not associated with reduced dopamine and high energy phosphate donors in a model of ataxia-telangiectasia

Identifieur interne : 000850 ( PascalFrancis/Checkpoint ); précédent : 000849; suivant : 000851

Progressive 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 :

RBID : Pascal:04-0345628

Descripteurs français

English descriptors

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.


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Pascal:04-0345628

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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>
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<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
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<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>
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<sup>+</sup>
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<sup>-/-</sup>
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<s5>03</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE">
<s0>Voie nigrostriatale</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG">
<s0>Nigrostriatal pathway</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA">
<s0>Vía nigroestriatal</s0>
<s5>04</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE">
<s0>NAD
<sup>+</sup>
ADP-ribosyltransferase</s0>
<s2>NK</s2>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG">
<s0>NAD
<sup>+</sup>
ADP-ribosyltransferase</s0>
<s2>NK</s2>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA">
<s0>NAD
<sup>+</sup>
ADP-ribosyltransferase</s0>
<s2>NK</s2>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE">
<s0>Tyrosine 3-monooxygenase</s0>
<s2>FE</s2>
<s5>06</s5>
<s6>Tyrosine «3»-monooxygenase</s6>
</fC03>
<fC03 i1="06" i2="X" l="ENG">
<s0>Tyrosine 3-monooxygenase</s0>
<s2>FE</s2>
<s5>06</s5>
<s6>Tyrosine «3»-monooxygenase</s6>
</fC03>
<fC03 i1="06" i2="X" l="SPA">
<s0>Tyrosine 3-monooxygenase</s0>
<s2>FE</s2>
<s5>06</s5>
<s6>Tyrosine «3»-monooxygenase</s6>
</fC03>
<fC03 i1="07" i2="X" l="FRE">
<s0>Coordination sensorimotrice</s0>
<s5>08</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG">
<s0>Sensorimotor coordination</s0>
<s5>08</s5>
</fC03>
<fC03 i1="07" i2="X" l="SPA">
<s0>Coordinación sensoriomotora</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="FRE">
<s0>Ataxie télangiectasie</s0>
<s5>09</s5>
</fC03>
<fC03 i1="08" i2="X" l="ENG">
<s0>Ataxia telangiectasia</s0>
<s5>09</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA">
<s0>Ataxia telangiectasia</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE">
<s0>Posture</s0>
<s5>10</s5>
</fC03>
<fC03 i1="09" i2="X" l="ENG">
<s0>Posture</s0>
<s5>10</s5>
</fC03>
<fC03 i1="09" i2="X" l="SPA">
<s0>Postura</s0>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="FRE">
<s0>Cervelet</s0>
<s5>11</s5>
</fC03>
<fC03 i1="10" i2="X" l="ENG">
<s0>Cerebellum</s0>
<s5>11</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA">
<s0>Cerebelo</s0>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="FRE">
<s0>Parkinson maladie</s0>
<s5>12</s5>
</fC03>
<fC03 i1="11" i2="X" l="ENG">
<s0>Parkinson disease</s0>
<s5>12</s5>
</fC03>
<fC03 i1="11" i2="X" l="SPA">
<s0>Parkinson enfermedad</s0>
<s5>12</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE">
<s0>Souris</s0>
<s5>54</s5>
</fC03>
<fC03 i1="12" i2="X" l="ENG">
<s0>Mouse</s0>
<s5>54</s5>
</fC03>
<fC03 i1="12" i2="X" l="SPA">
<s0>Ratón</s0>
<s5>54</s5>
</fC03>
<fC03 i1="13" i2="X" l="FRE">
<s0>Animal</s0>
<s5>69</s5>
</fC03>
<fC03 i1="13" i2="X" l="ENG">
<s0>Animal</s0>
<s5>69</s5>
</fC03>
<fC03 i1="13" i2="X" l="SPA">
<s0>Animal</s0>
<s5>69</s5>
</fC03>
<fC03 i1="14" i2="X" l="FRE">
<s0>NAD
<sup>+</sup>
</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC03 i1="14" i2="X" l="ENG">
<s0>NAD
<sup>+</sup>
</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE">
<s0>Pentosyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG">
<s0>Pentosyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA">
<s0>Pentosyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE">
<s0>Glycosyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG">
<s0>Glycosyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA">
<s0>Glycosyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE">
<s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG">
<s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA">
<s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE">
<s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="ENG">
<s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="SPA">
<s0>Enzima</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="FRE">
<s0>Oxidoreductases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="ENG">
<s0>Oxidoreductases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="SPA">
<s0>Oxidoreductases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="06" i2="X" l="FRE">
<s0>Neurotransmetteur</s0>
<s5>20</s5>
</fC07>
<fC07 i1="06" i2="X" l="ENG">
<s0>Neurotransmitter</s0>
<s5>20</s5>
</fC07>
<fC07 i1="06" i2="X" l="SPA">
<s0>Neurotransmisor</s0>
<s5>20</s5>
</fC07>
<fC07 i1="07" i2="X" l="FRE">
<s0>Catécholamine</s0>
<s5>21</s5>
</fC07>
<fC07 i1="07" i2="X" l="ENG">
<s0>Catecholamine</s0>
<s5>21</s5>
</fC07>
<fC07 i1="07" i2="X" l="SPA">
<s0>Catecolamina</s0>
<s5>21</s5>
</fC07>
<fC07 i1="08" i2="X" l="FRE">
<s0>Système nerveux pathologie</s0>
<s5>38</s5>
</fC07>
<fC07 i1="08" i2="X" l="ENG">
<s0>Nervous system diseases</s0>
<s5>38</s5>
</fC07>
<fC07 i1="08" i2="X" l="SPA">
<s0>Sistema nervioso patología</s0>
<s5>38</s5>
</fC07>
<fC07 i1="09" i2="X" l="FRE">
<s0>Appareil circulatoire pathologie</s0>
<s5>39</s5>
</fC07>
<fC07 i1="09" i2="X" l="ENG">
<s0>Cardiovascular disease</s0>
<s5>39</s5>
</fC07>
<fC07 i1="09" i2="X" l="SPA">
<s0>Aparato circulatorio patología</s0>
<s5>39</s5>
</fC07>
<fC07 i1="10" i2="X" l="FRE">
<s0>Vaisseau sanguin pathologie</s0>
<s5>40</s5>
</fC07>
<fC07 i1="10" i2="X" l="ENG">
<s0>Vascular disease</s0>
<s5>40</s5>
</fC07>
<fC07 i1="10" i2="X" l="SPA">
<s0>Vaso sanguíneo patología</s0>
<s5>40</s5>
</fC07>
<fC07 i1="11" i2="X" l="FRE">
<s0>Oeil pathologie</s0>
<s5>41</s5>
</fC07>
<fC07 i1="11" i2="X" l="ENG">
<s0>Eye disease</s0>
<s5>41</s5>
</fC07>
<fC07 i1="11" i2="X" l="SPA">
<s0>Ojo patología</s0>
<s5>41</s5>
</fC07>
<fC07 i1="12" i2="X" l="FRE">
<s0>Peau pathologie</s0>
<s5>42</s5>
</fC07>
<fC07 i1="12" i2="X" l="ENG">
<s0>Skin disease</s0>
<s5>42</s5>
</fC07>
<fC07 i1="12" i2="X" l="SPA">
<s0>Piel patología</s0>
<s5>42</s5>
</fC07>
<fC07 i1="13" i2="X" l="FRE">
<s0>Immunopathologie</s0>
<s5>43</s5>
</fC07>
<fC07 i1="13" i2="X" l="ENG">
<s0>Immunopathology</s0>
<s5>43</s5>
</fC07>
<fC07 i1="13" i2="X" l="SPA">
<s0>Inmunopatología</s0>
<s5>43</s5>
</fC07>
<fC07 i1="14" i2="X" l="FRE">
<s0>Maladie héréditaire</s0>
<s5>44</s5>
</fC07>
<fC07 i1="14" i2="X" l="ENG">
<s0>Genetic disease</s0>
<s5>44</s5>
</fC07>
<fC07 i1="14" i2="X" l="SPA">
<s0>Enfermedad hereditaria</s0>
<s5>44</s5>
</fC07>
<fC07 i1="15" i2="X" l="FRE">
<s0>Système nerveux central pathologie</s0>
<s5>46</s5>
</fC07>
<fC07 i1="15" i2="X" l="ENG">
<s0>Central nervous system disease</s0>
<s5>46</s5>
</fC07>
<fC07 i1="15" i2="X" l="SPA">
<s0>Sistema nervosio central patología</s0>
<s5>46</s5>
</fC07>
<fC07 i1="16" i2="X" l="FRE">
<s0>Encéphale pathologie</s0>
<s5>47</s5>
</fC07>
<fC07 i1="16" i2="X" l="ENG">
<s0>Cerebral disorder</s0>
<s5>47</s5>
</fC07>
<fC07 i1="16" i2="X" l="SPA">
<s0>Encéfalo patología</s0>
<s5>47</s5>
</fC07>
<fC07 i1="17" i2="X" l="FRE">
<s0>Extrapyramidal syndrome</s0>
<s5>48</s5>
</fC07>
<fC07 i1="17" i2="X" l="ENG">
<s0>Extrapyramidal syndrome</s0>
<s5>48</s5>
</fC07>
<fC07 i1="17" i2="X" l="SPA">
<s0>Extrapiramidal síndrome</s0>
<s5>48</s5>
</fC07>
<fC07 i1="18" i2="X" l="FRE">
<s0>Maladie dégénérative</s0>
<s5>49</s5>
</fC07>
<fC07 i1="18" i2="X" l="ENG">
<s0>Degenerative disease</s0>
<s5>49</s5>
</fC07>
<fC07 i1="18" i2="X" l="SPA">
<s0>Enfermedad degenerativa</s0>
<s5>49</s5>
</fC07>
<fC07 i1="19" i2="X" l="FRE">
<s0>Rodentia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="19" i2="X" l="ENG">
<s0>Rodentia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="19" i2="X" l="SPA">
<s0>Rodentia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="20" i2="X" l="FRE">
<s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="20" i2="X" l="ENG">
<s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="20" i2="X" l="SPA">
<s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="21" i2="X" l="FRE">
<s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="21" i2="X" l="ENG">
<s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="21" i2="X" l="SPA">
<s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fN21>
<s1>201</s1>
</fN21>
</pA>
</standard>
</inist>
<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>

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