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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Urs, Nikhil M. Daigle, Tanya L. Peterson, Sean M. Bass, Caroline E. Gainetdinov, Raul R. Bezard, Erwan Bido, Simone Caron, Marc G. |
| Description | Author Affiliation: Urs NM ( Departments of Cell Biology, marc.caron@dm.duke.edu nikhil.urs@duke.edu.); Bido S ( Institut des Maladies Neurodégénératives, UMR 5293, Université de Bordeaux, 33000 Bordeaux, France); Peterson SM ( Departments of Cell Biology.); Daigle TL ( Departments of Cell Biology.); Bass CE ( Department of Pharmacology and Toxicology, University at Buffalo, The State Uiversity of New York, Buffalo, NY 14260); Gainetdinov RR ( Departments of Cell Biology, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, 199034, Russia.); Bezard E ( Institut des Maladies Neurodégénératives, UMR 5293, Université de Bordeaux, 33000 Bordeaux, France); Caron MG ( Departments of Cell Biology, Medicine, and Neurobiology, Duke University Medical Center, Durham NC 27710); |
| Abstract | Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-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. ß-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 ß-arrestins in PD L-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 ß-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of ß-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, ß-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-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 ß-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 19 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Arrestins Metabolism Dyskinesias Levodopa Chemistry Parkinson Disease Drug Therapy 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Animals Genetics Behavior, Animal Disease Models, Animal Dopamine Dyskinesia, Drug-Induced Gene Deletion Macaca Mice Mice, Inbred C57BL Mice, Knockout Neurons Oxidopamine Rats, Sprague-Dawley Signal Transduction Up-Regulation Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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