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Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile\n                    <jats:italic>Dyt1<\/jats:italic>\n                    mice. This occurs through increased lysosomal degradation, controlled by competition between \u03b2\u2010arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9\u20102 and spinophilin. Further, we show that genetic depletion of RGS9\u20102 mimics the D2 receptor loss of\n                    <jats:italic>DYT1<\/jats:italic>\n                    dystonia striatum, whereas RGS9\u20102 overexpression rescues both receptor levels and electrophysiological responses in\n                    <jats:italic>Dyt1<\/jats:italic>\n                    striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in\n                    <jats:italic>Dyt1<\/jats:italic>\n                    mice and in turn explains why dopaminergic drugs lack efficacy in\n                    <jats:italic>DYT1<\/jats:italic>\n                    patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease\u2010modifying therapeutics to this incurable neurological disorder.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201809283","type":"journal-article","created":{"date-parts":[[2018,12,14]],"date-time":"2018-12-14T09:56:44Z","timestamp":1544781404000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["RGS9\u20102 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5940-9028","authenticated-orcid":false,"given":"Paola","family":"Bonsi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Ponterio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Vanni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Tassone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Sciamanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Migliarini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppina","family":"Martella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Meringolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1723-9045","authenticated-orcid":false,"given":"Benjamin","family":"Dehay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyne","family":"Doudnikoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venetia","family":"Zachariou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-5728","authenticated-orcid":false,"given":"Rose E","family":"Goodchild","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola B","family":"Mercuri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"D'Amelio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Pasqualetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0410-4638","authenticated-orcid":false,"given":"Erwan","family":"Bezard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8432-594X","authenticated-orcid":false,"given":"Antonio","family":"Pisani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,12,14]]},"reference":[{"key":"BFEMMM201809283_CR1","doi-asserted-by":"crossref","first-page":"14117","DOI":"10.1523\/JNEUROSCI.3884-07.2007","volume":"27","author":"GR Anderson","year":"2007","unstructured":"Anderson GR, Lujan R, Semenov A, Pravetoni M, Posokhova EN, Song JH, Uversky V, Chen CK, Wickman K, Martemyanov KA (2007a) Expression and localization of RGS9\u20102\/G 5\/R7BP complex in\u00a0vivo is set by dynamic control of its constitutive degradation by cellular cysteine proteases. 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