RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models
Abstract Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early‐onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorl...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809283 |
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| author | Paola Bonsi Giulia Ponterio Valentina Vanni Annalisa Tassone Giuseppe Sciamanna Sara Migliarini Giuseppina Martella Maria Meringolo Benjamin Dehay Evelyne Doudnikoff Venetia Zachariou Rose E Goodchild Nicola B Mercuri Marcello D'Amelio Massimo Pasqualetti Erwan Bezard Antonio Pisani |
| author_facet | Paola Bonsi Giulia Ponterio Valentina Vanni Annalisa Tassone Giuseppe Sciamanna Sara Migliarini Giuseppina Martella Maria Meringolo Benjamin Dehay Evelyne Doudnikoff Venetia Zachariou Rose E Goodchild Nicola B Mercuri Marcello D'Amelio Massimo Pasqualetti Erwan Bezard Antonio Pisani |
| author_sort | Paola Bonsi |
| collection | DOAJ |
| description | Abstract Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early‐onset DYT1 dystonia. 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 Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β‐arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9‐2 and spinophilin. Further, we show that genetic depletion of RGS9‐2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9‐2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease‐modifying therapeutics to this incurable neurological disorder. |
| format | Article |
| id | doaj-art-aead3905e88349bb9ef74acccad80c03 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-aead3905e88349bb9ef74acccad80c032025-08-20T02:39:24ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-12-0111111910.15252/emmm.201809283RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse modelsPaola Bonsi0Giulia Ponterio1Valentina Vanni2Annalisa Tassone3Giuseppe Sciamanna4Sara Migliarini5Giuseppina Martella6Maria Meringolo7Benjamin Dehay8Evelyne Doudnikoff9Venetia Zachariou10Rose E Goodchild11Nicola B Mercuri12Marcello D'Amelio13Massimo Pasqualetti14Erwan Bezard15Antonio Pisani16Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaLaboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaLaboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaLaboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaLaboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaUnit of Cell and Developmental Biology, Department of Biology, University of PisaLaboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaLaboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaUniversité de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Neurosciences, VIB‐KU Leuven Center for Brain and Disease Research, KU LeuvenLaboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaLaboratory Molecular Neurosciences, IRCCS Fondazione Santa LuciaUnit of Cell and Developmental Biology, Department of Biology, University of PisaUniversité de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa LuciaAbstract Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early‐onset DYT1 dystonia. 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 Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β‐arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9‐2 and spinophilin. Further, we show that genetic depletion of RGS9‐2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9‐2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease‐modifying therapeutics to this incurable neurological disorder.https://doi.org/10.15252/emmm.201809283beta‐arrestinlysosomal degradationstriatum |
| spellingShingle | Paola Bonsi Giulia Ponterio Valentina Vanni Annalisa Tassone Giuseppe Sciamanna Sara Migliarini Giuseppina Martella Maria Meringolo Benjamin Dehay Evelyne Doudnikoff Venetia Zachariou Rose E Goodchild Nicola B Mercuri Marcello D'Amelio Massimo Pasqualetti Erwan Bezard Antonio Pisani RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models EMBO Molecular Medicine beta‐arrestin lysosomal degradation striatum |
| title | RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models |
| title_full | RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models |
| title_fullStr | RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models |
| title_full_unstemmed | RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models |
| title_short | RGS9‐2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models |
| title_sort | rgs9 2 rescues dopamine d2 receptor levels and signaling in dyt1 dystonia mouse models |
| topic | beta‐arrestin lysosomal degradation striatum |
| url | https://doi.org/10.15252/emmm.201809283 |
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