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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Targeting β-arrestin2 in the treatment of <sc>l</sc>-DOPA–induced dyskinesia in Parkinson’s disease</title><author><name sortKey="Urs, Nikhil M" sort="Urs, Nikhil M" uniqKey="Urs N" first="Nikhil M." last="Urs">Nikhil M. Urs</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bido, Simone" sort="Bido, Simone" uniqKey="Bido S" first="Simone" last="Bido">Simone Bido</name><affiliation><nlm:aff id="aff4">Institut des Maladies Neurodégénératives, UMR 5293,<institution>Université de Bordeaux</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Institut des Maladies Neurodégénératives, UMR 5293,<institution>CNRS</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Peterson, Sean M" sort="Peterson, Sean M" uniqKey="Peterson S" first="Sean M." last="Peterson">Sean M. Peterson</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Daigle, Tanya L" sort="Daigle, Tanya L" uniqKey="Daigle T" first="Tanya L." last="Daigle">Tanya L. Daigle</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bass, Caroline E" sort="Bass, Caroline E" uniqKey="Bass C" first="Caroline E." last="Bass">Caroline E. Bass</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Pharmacology and Toxicology,<institution>University at Buffalo</institution>, The State Uiversity of New York, Buffalo,<addr-line>NY</addr-line> 14260</nlm:aff></affiliation></author><author><name sortKey="Gainetdinov, Raul R" sort="Gainetdinov, Raul R" uniqKey="Gainetdinov R" first="Raul R." last="Gainetdinov">Raul R. Gainetdinov</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institute of Translational Biomedicine,<institution>St. Petersburg State University</institution>, St. Petersburg, 199034,<country>Russia</country></nlm:aff></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation><nlm:aff id="aff4">Institut des Maladies Neurodégénératives, UMR 5293,<institution>Université de Bordeaux</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Institut des Maladies Neurodégénératives, UMR 5293,<institution>CNRS</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Caron, Marc G" sort="Caron, Marc G" uniqKey="Caron M" first="Marc G." last="Caron">Marc G. Caron</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff2">Medicine</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Neurobiology,<institution>Duke University Medical Center</institution>, Durham<addr-line>NC</addr-line> 27710;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25918399</idno><idno type="pmc">4434696</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434696</idno><idno type="RBID">PMC:4434696</idno><idno type="doi">10.1073/pnas.1502740112</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000050</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000050</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Targeting β-arrestin2 in the treatment of <sc>l</sc>-DOPA–induced dyskinesia in Parkinson’s disease</title><author><name sortKey="Urs, Nikhil M" sort="Urs, Nikhil M" uniqKey="Urs N" first="Nikhil M." last="Urs">Nikhil M. Urs</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bido, Simone" sort="Bido, Simone" uniqKey="Bido S" first="Simone" last="Bido">Simone Bido</name><affiliation><nlm:aff id="aff4">Institut des Maladies Neurodégénératives, UMR 5293,<institution>Université de Bordeaux</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Institut des Maladies Neurodégénératives, UMR 5293,<institution>CNRS</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Peterson, Sean M" sort="Peterson, Sean M" uniqKey="Peterson S" first="Sean M." last="Peterson">Sean M. Peterson</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Daigle, Tanya L" sort="Daigle, Tanya L" uniqKey="Daigle T" first="Tanya L." last="Daigle">Tanya L. Daigle</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bass, Caroline E" sort="Bass, Caroline E" uniqKey="Bass C" first="Caroline E." last="Bass">Caroline E. Bass</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Pharmacology and Toxicology,<institution>University at Buffalo</institution>, The State Uiversity of New York, Buffalo,<addr-line>NY</addr-line> 14260</nlm:aff></affiliation></author><author><name sortKey="Gainetdinov, Raul R" sort="Gainetdinov, Raul R" uniqKey="Gainetdinov R" first="Raul R." last="Gainetdinov">Raul R. Gainetdinov</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institute of Translational Biomedicine,<institution>St. Petersburg State University</institution>, St. Petersburg, 199034,<country>Russia</country></nlm:aff></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation><nlm:aff id="aff4">Institut des Maladies Neurodégénératives, UMR 5293,<institution>Université de Bordeaux</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Institut des Maladies Neurodégénératives, UMR 5293,<institution>CNRS</institution>, 33000 Bordeaux,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Caron, Marc G" sort="Caron, Marc G" uniqKey="Caron M" first="Marc G." last="Caron">Marc G. Caron</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff2">Medicine</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Neurobiology,<institution>Duke University Medical Center</institution>, Durham<addr-line>NC</addr-line> 27710;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>β-Arrestins are unique proteins that have multiple cellular functions such as G protein-coupled receptor signal desensitization, protein trafficking and signaling molecule scaffolding. Treatment of Parkinson’s disease (PD) motor symptoms by <sc>l</sc>-3,4-dihydroxyphenylalanine (<sc>l</sc>-DOPA) has been hampered by abnormal involuntary movements or dyskinetic side effects. The cause of these dyskinesias has been attributed to receptor supersensitivity and uncontrolled neuronal excitability. Here we demonstrate in multiple preclinical models of <sc>l</sc>-DOPA–induced dyskinesias and PD that expression levels of β-arrestin2 can alter manifestation of these dyskinesias by reducing receptor supersensitivity while maintaining the therapeutic effect of <sc>l</sc>-DOPA. Thus novel drugs that increase β-arrestin–dependent function at dopamine receptors may be useful in ameliorating PD motor symptoms without inducing dyskinesias.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25918399</article-id><article-id pub-id-type="pmc">4434696</article-id><article-id pub-id-type="publisher-id">201502740</article-id><article-id pub-id-type="doi">10.1073/pnas.1502740112</article-id><article-categories><subj-group subj-group-type="heading"><subject>PNAS Plus</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Neuroscience</subject></subj-group></subj-group><series-title>PNAS Plus</series-title></article-categories><title-group><article-title>Targeting β-arrestin2 in the treatment of <sc>l</sc>-DOPA–induced dyskinesia in Parkinson’s disease</article-title><alt-title alt-title-type="short">Striatal β-arrestin2 overexpression reduces LIDs</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Urs</surname><given-names>Nikhil M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bido</surname><given-names>Simone</given-names></name><xref ref-type="aff" rid="aff4"><sup>b</sup></xref><xref ref-type="aff" rid="aff5"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peterson</surname><given-names>Sean M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Daigle</surname><given-names>Tanya L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bass</surname><given-names>Caroline E.</given-names></name><xref ref-type="aff" rid="aff6"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gainetdinov</surname><given-names>Raul R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff7"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bezard</surname><given-names>Erwan</given-names></name><xref ref-type="aff" rid="aff4"><sup>b</sup></xref><xref ref-type="aff" rid="aff5"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Caron</surname><given-names>Marc G.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>f</sup></xref><xref ref-type="aff" rid="aff3"><sup>g</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1">Departments of<sup>a</sup>Cell Biology,</aff><aff id="aff2"><sup>f</sup>Medicine, and</aff><aff id="aff3"><sup>g</sup>Neurobiology,<institution>Duke University Medical Center</institution>, Durham<addr-line>NC</addr-line> 27710;</aff><aff id="aff4"><sup>b</sup>Institut des Maladies Neurodégénératives, UMR 5293,<institution>Université de Bordeaux</institution>, 33000 Bordeaux,<country>France</country>;</aff><aff id="aff5"><sup>c</sup>Institut des Maladies Neurodégénératives, UMR 5293,<institution>CNRS</institution>, 33000 Bordeaux,<country>France</country>;</aff><aff id="aff6"><sup>d</sup>Department of Pharmacology and Toxicology,<institution>University at Buffalo</institution>, The State Uiversity of New York, Buffalo,<addr-line>NY</addr-line> 14260; and</aff><aff id="aff7"><sup>e</sup>Institute of Translational Biomedicine,<institution>St. Petersburg State University</institution>, St. Petersburg, 199034,<country>Russia</country></aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence may be addressed. Email: <email>marc.caron@dm.duke.edu</email> or <email>nikhil.urs@duke.edu</email>.</corresp><fn fn-type="edited-by"><p>Edited by Richard D. Palmiter, University of Washington, Seattle, WA, and approved March 24, 2015 (received for review February 9, 2015)</p></fn><fn fn-type="con"><p>Author contributions: N.M.U., E.B., and M.G.C. designed research; N.M.U., S.B., and S.M.P. performed research; T.L.D., C.E.B., and R.R.G. contributed new reagents/analytic tools; N.M.U., S.B., S.M.P., R.R.G., and E.B. analyzed data; and N.M.U., S.B., E.B., and M.G.C. wrote the paper.</p></fn><fn fn-type="present-address" id="fn1"><p><sup>2</sup>Present address: Allen Institute for Brain Science, 551 N 34th St., Seattle, WA 98103.</p></fn></author-notes><pub-date pub-type="ppub"><day>12</day><month>5</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>27</day><month>4</month><year>2015</year></pub-date><volume>112</volume><issue>19</issue><fpage>E2517</fpage><lpage>E2526</lpage><self-uri xlink:title="pdf" xlink:href="pnas.201502740.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>β-Arrestins are unique proteins that have multiple cellular functions such as G protein-coupled receptor signal desensitization, protein trafficking and signaling molecule scaffolding. Treatment of Parkinson’s disease (PD) motor symptoms by <sc>l</sc>-3,4-dihydroxyphenylalanine (<sc>l</sc>-DOPA) has been hampered by abnormal involuntary movements or dyskinetic side effects. The cause of these dyskinesias has been attributed to receptor supersensitivity and uncontrolled neuronal excitability. Here we demonstrate in multiple preclinical models of <sc>l</sc>-DOPA–induced dyskinesias and PD that expression levels of β-arrestin2 can alter manifestation of these dyskinesias by reducing receptor supersensitivity while maintaining the therapeutic effect of <sc>l</sc>-DOPA. Thus novel drugs that increase β-arrestin–dependent function at dopamine receptors may be useful in ameliorating PD motor symptoms without inducing dyskinesias.</p></abstract><abstract><p>Parkinson’s disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor <sc>l</sc>-3,4-dihydroxyphenylalanine (<sc>l</sc>-DOPA), but its prolonged use causes dyskinesias referred to as <sc>l</sc>-DOPA–induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD <sc>l</sc>-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson’s symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic <sc>l</sc>-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine–treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of <sc>l</sc>-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.</p></abstract><kwd-group><kwd><sc>l</sc>-DOPA</kwd><kwd>dyskinesia</kwd><kwd>beta-arrestin</kwd><kwd>dopamine receptors</kwd><kwd>biased signaling</kwd></kwd-group><funding-group><award-group id="gs1"><funding-source id="sp1">HHS | NIH | National Institute of Mental Health (NIMH)<named-content content-type="funder-id">100000025</named-content></funding-source><award-id rid="sp1">5R37MH073853</award-id></award-group><award-group id="gs2"><funding-source id="sp2">HHS | NIH | National Institute on Drug Abuse (NIDA)<named-content content-type="funder-id">100000026</named-content></funding-source><award-id rid="sp2">K01DA024763</award-id></award-group><award-group id="gs3"><funding-source id="sp3">Michael J. Fox Foundation for Parkinson's Research (MJFF)<named-content content-type="funder-id">100000864</named-content></funding-source><award-id rid="sp3">TV2011</award-id></award-group></funding-group><counts><page-count count="10"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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