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This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, <jats:italic>in\u00a0vitro<\/jats:italic>, that dopaminergic D2 receptor stimulation acted in synergy with expanded huntingtin to increase aggregates formation and striatal death through activation of the Rho\/<jats:styled-content style=\"fixed-case\">ROCK<\/jats:styled-content> signaling pathway. <jats:italic>In vivo<\/jats:italic>, in a lentiviral\u2010mediated model of expanded huntingtin expression in the rat striatum, we found that the D2 antagonist haloperidol protects striatal neurons against expanded huntingtin\u2010mediated toxicity. Two variant transcripts are generated by alternative splicing of the of D2 receptor gene, the D2R\u2010Long and the D2R\u2010Short, which are thought to play different functional roles. We show herein that overexpression of D2R\u2010Short, but not D2R\u2010Long in cell lines is associated with activation of the RhoA\/<jats:styled-content style=\"fixed-case\">ROCK<\/jats:styled-content> signaling pathway. In striatal neurons in culture, the selective D2 agonist Quinpirole triggers phosphorylation of cofilin, a downstream effector of <jats:styled-content style=\"fixed-case\">ROCK<\/jats:styled-content>, which is abrogated by si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>s that knockdown both D2R\u2010Long and D2R\u2010Short, but not by si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>s targeting D2R\u2010Long alone. Aggregate formation and neuronal death induced by expanded huntingtin, were potentiated by Quinpirole. This D2 agonist\u2010mediated effect was selectively inhibited by the si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> targeting both D2R\u2010Long and D2R\u2010Short but not D2R\u2010Long alone. Our data provide evidence for a specific coupling of D2R\u2010Short to the RhoA\/<jats:styled-content style=\"fixed-case\">ROCK<\/jats:styled-content>\/cofilin pathway, and its involvement in striatal vulnerability to expanded huntingtin. A new route for targeting Rho\u2010<jats:styled-content style=\"fixed-case\">ROCK<\/jats:styled-content> signaling in Huntington's disease is unraveled with our findings.<\/jats:p>","DOI":"10.1111\/ejn.13415","type":"journal-article","created":{"date-parts":[[2016,9,26]],"date-time":"2016-09-26T13:05:54Z","timestamp":1474895154000},"page":"198-206","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Coupling of D2R Short but not D2R Long receptor isoform to the Rho\/<scp>ROCK<\/scp> signaling pathway renders striatal neurons vulnerable to mutant huntingtin"],"prefix":"10.1111","volume":"45","author":[{"given":"Beatriz","family":"Galan\u2010Rodriguez","sequence":"first","affiliation":[{"name":"UMRS\u2010INSERM1130 Neurosciences Paris Seine Paris France"},{"name":"Departamento de Fisiolog\u00eda M\u00e9dica y Biof\u00edsica Universidad de Sevilla Sevilla Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elodie","family":"Martin","sequence":"additional","affiliation":[{"name":"INSERM UMRS_1127\/UPMC\/CNRS UMR7225 Institut du Cerveau et de la Moelle H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Brouillet","sequence":"additional","affiliation":[{"name":"CEA, DSV, I\u00b2BM Molecular Imaging Research Center (MIRCen) Fontenay\u2010aux\u2010Roses France"},{"name":"Neurodegenerative Diseases Laboratory CNRS CEA URA 2210 Fontenay\u2010aux\u2010Roses France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"D\u00e9glon","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences (DNC) Laboratory of Cellular and Molecular Neurotherapies (LNCM) Lausanne University Medical School (CHUV) Lausanne Switzerland"},{"name":"Neuroscience Research Center (CRN) Laboratory of Cellular and Molecular Neurotherapies (LNCM) Lausanne University Medical School (CHUV) Lausanne Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Betuing","sequence":"additional","affiliation":[{"name":"UMRS\u2010INSERM1130 Neurosciences Paris Seine Paris France"},{"name":"UMR CNRS\u20108246 Paris France"},{"name":"Sorbonne Universit\u00e9 UM119 Universit\u00e9 Pierre and Marie Curie\u2010Paris 6 9 quai Saint Bernard 75005 Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jocelyne","family":"Caboche","sequence":"additional","affiliation":[{"name":"UMRS\u2010INSERM1130 Neurosciences Paris Seine Paris France"},{"name":"UMR CNRS\u20108246 Paris France"},{"name":"Sorbonne Universit\u00e9 UM119 Universit\u00e9 Pierre and Marie Curie\u2010Paris 6 9 quai Saint Bernard 75005 Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,10,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410310412"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(02)02404-2"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2891-04.2004"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412924200"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809229200"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-7-43"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.05.012"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn033"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2002.0518"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.02.007"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502698102"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.07.028"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1831768100"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2008.12.002"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008287"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2004.05.054"},{"key":"e_1_2_6_18_1","doi-asserted-by":"crossref","first-page":"4533","DOI":"10.1523\/JNEUROSCI.15-06-04533.1995","article-title":"Dopamine\u2010modulated potassium channels on rat striatal neurons: specific activation and cellular expression","volume":"15","author":"Greif G.J.","year":"1995","journal-title":"J. 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