期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 19, 页码 E2517-E2526出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1502740112
关键词
L-DOPA; dyskinesia; beta-arrestin; dopamine receptors; biased signaling
资金
- Michael J. Fox Foundation
- National Institutes of Health [5R37MH073853, K01DA024763]
- Pall Family Foundation
- Sydney R. Bear Prize
- Agence Nationale de la Recherche Grant [ANR-12-BSV4-0001-01]
- LABEX BRAIN [ANR-10-LABX-43]
- Russian Science Foundation [14-50-00069]
- Russian Science Foundation [14-50-00069] Funding Source: Russian Science Foundation
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 proteinmediated signaling through DA receptors. beta-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 beta-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 beta-arrestin2 significantly limits the beneficial locomotor effectswhilemarkedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of beta-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 non-human primates, beta-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 beta-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.
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