D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease
Identifieur interne : 001599 ( Main/Exploration ); précédent : 001598; suivant : 001600D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease
Auteurs : Soyeon Lim [États-Unis] ; Adrianne S. Chesser [États-Unis] ; Jonathan C. Grima [États-Unis] ; Phillip M. Rappold [États-Unis] ; David Blum [France] ; Serge Przedborski [États-Unis] ; Kim Tieu [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
Abnormalities in mitochondrial function and epigenetic regulation are thought to be instrumental in Huntington's disease (HD), a fatal genetic disorder caused by an expanded polyglutamine track in the protein huntingtin. Given the lack of effective therapies for HD, we sought to assess the neuroprotective properties of the mitochondrial energizing ketone body, D-β-hydroxybutyrate (DβHB), in the 3-nitropropionic acid (3-NP) toxic and the R6/2 genetic model of HD. In mice treated with 3-NP, a complex II inhibitor, infusion of DβHB attenuates motor deficits, striatal lesions, and microgliosis in this model of toxin induced-striatal neurodegeneration. In transgenic R6/2 mice, infusion of DβHB extends life span, attenuates motor deficits, and prevents striatal histone deacetylation. In PC12 cells with inducible expression of mutant huntingtin protein, we further demonstrate that DβHB prevents histone deacetylation
Url:
DOI: 10.1371/journal.pone.0024620
PubMed: 21931779
PubMed Central: 3171454
Affiliations:
- France, États-Unis
- Hauts-de-France, Nord-Pas-de-Calais, État de New York
- Lille, New York
- Université Columbia
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type="main">D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease</title><author><name sortKey="Lim, Soyeon" sort="Lim, Soyeon" uniqKey="Lim S" first="Soyeon" last="Lim">Soyeon Lim</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Chesser, Adrianne S" sort="Chesser, Adrianne S" uniqKey="Chesser A" first="Adrianne S." last="Chesser">Adrianne S. 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Rappold</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Blum, David" sort="Blum, David" uniqKey="Blum D" first="David" last="Blum">David Blum</name><affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>Jean-Pierre Aubert Research Centre, Universite Lille-Nord de France, IMPRT, Lille, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Jean-Pierre Aubert Research Centre, Universite Lille-Nord de France, IMPRT, Lille</wicri:regionArea><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff3"><addr-line>Alzheimer and Tauopathies, Inserm UMR-U837, Lille, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Alzheimer and Tauopathies, Inserm UMR-U837, Lille</wicri:regionArea><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff4"><addr-line>CHRU, Lille, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>CHRU, Lille</wicri:regionArea><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Przedborski, Serge" sort="Przedborski, Serge" uniqKey="Przedborski S" first="Serge" last="Przedborski">Serge Przedborski</name><affiliation wicri:level="4"><nlm:aff id="aff5"><addr-line>Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Motor Neuron Biology and Disease, Columbia University, New York, New York</wicri:regionArea><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff6"><addr-line>Departments of Neurology, Pathology and Cell Biology, Columbia University, New York, New York, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Neurology, Pathology and Cell Biology, Columbia University, New York, New York</wicri:regionArea><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation></author><author><name sortKey="Tieu, Kim" sort="Tieu, Kim" uniqKey="Tieu K" first="Kim" last="Tieu">Kim Tieu</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Abnormalities in mitochondrial function and epigenetic regulation are thought to be instrumental in Huntington's disease (HD), a fatal genetic disorder caused by an expanded polyglutamine track in the protein huntingtin. Given the lack of effective therapies for HD, we sought to assess the neuroprotective properties of the mitochondrial energizing ketone body, D-β-hydroxybutyrate (DβHB), in the 3-nitropropionic acid (3-NP) toxic and the R6/2 genetic model of HD. In mice treated with 3-NP, a complex II inhibitor, infusion of DβHB attenuates motor deficits, striatal lesions, and microgliosis in this model of toxin induced-striatal neurodegeneration. In transgenic R6/2 mice, infusion of DβHB extends life span, attenuates motor deficits, and prevents striatal histone deacetylation. In PC12 cells with inducible expression of mutant huntingtin protein, we further demonstrate that DβHB prevents histone deacetylation <italic>via</italic> a mechanism independent of its mitochondrial effects and independent of histone deacetylase inhibition. These pre-clinical findings suggest that by simultaneously targeting the mitochondrial and the epigenetic abnormalities associated with mutant huntingtin, DβHB may be a valuable therapeutic agent for HD.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Vonsattel, Jp" uniqKey="Vonsattel J">JP Vonsattel</name></author><author><name sortKey="Keller, C" uniqKey="Keller C">C Keller</name></author><author><name sortKey="Cortes Ramirez, Ep" uniqKey="Cortes Ramirez E">EP Cortes Ramirez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brouillet, E" uniqKey="Brouillet E">E Brouillet</name></author><author><name sortKey="Jacquard, C" uniqKey="Jacquard C">C Jacquard</name></author><author><name sortKey="Bizat, N" uniqKey="Bizat N">N Bizat</name></author><author><name sortKey="Blum, D" uniqKey="Blum D">D Blum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kazantsev, Ag" 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Beppu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sokoloff, L" uniqKey="Sokoloff L">L Sokoloff</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>France</li><li>États-Unis</li></country><region><li>Hauts-de-France</li><li>Nord-Pas-de-Calais</li><li>État de New York</li></region><settlement><li>Lille</li><li>New York</li></settlement><orgName><li>Université Columbia</li></orgName></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Lim, Soyeon" sort="Lim, Soyeon" uniqKey="Lim S" first="Soyeon" last="Lim">Soyeon Lim</name></region><name sortKey="Chesser, Adrianne S" sort="Chesser, Adrianne S" uniqKey="Chesser A" first="Adrianne S." last="Chesser">Adrianne S. Chesser</name><name sortKey="Grima, Jonathan C" sort="Grima, Jonathan C" uniqKey="Grima J" first="Jonathan C." last="Grima">Jonathan C. Grima</name><name sortKey="Przedborski, Serge" sort="Przedborski, Serge" uniqKey="Przedborski S" first="Serge" last="Przedborski">Serge Przedborski</name><name sortKey="Przedborski, Serge" sort="Przedborski, Serge" uniqKey="Przedborski S" first="Serge" last="Przedborski">Serge Przedborski</name><name sortKey="Rappold, Phillip M" sort="Rappold, Phillip M" uniqKey="Rappold P" first="Phillip M." last="Rappold">Phillip M. Rappold</name><name sortKey="Tieu, Kim" sort="Tieu, Kim" uniqKey="Tieu K" first="Kim" last="Tieu">Kim Tieu</name></country><country name="France"><region name="Hauts-de-France"><name sortKey="Blum, David" sort="Blum, David" uniqKey="Blum D" first="David" last="Blum">David Blum</name></region><name sortKey="Blum, David" sort="Blum, David" uniqKey="Blum D" first="David" last="Blum">David Blum</name><name sortKey="Blum, David" sort="Blum, David" uniqKey="Blum D" first="David" last="Blum">David Blum</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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