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Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease.

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. β-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 β-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 β-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 β-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, β-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 β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.
AuthorsNikhil M Urs, Simone Bido, Sean M Peterson, Tanya L Daigle, Caroline E Bass, Raul R Gainetdinov, Erwan Bezard, Marc G Caron
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 19 Pg. E2517-26 (May 12 2015) ISSN: 1091-6490 [Electronic] United States
PMID25918399 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Arrestins
  • beta-Arrestins
  • Levodopa
  • Oxidopamine
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Dopamine
Topics
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (chemistry)
  • Animals
  • Arrestins (genetics, metabolism)
  • Behavior, Animal
  • Disease Models, Animal
  • Dopamine (metabolism)
  • Dyskinesia, Drug-Induced (metabolism)
  • Dyskinesias (metabolism)
  • Gene Deletion
  • Levodopa (chemistry)
  • Macaca
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons (metabolism)
  • Oxidopamine (chemistry)
  • Parkinson Disease (drug therapy, metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Up-Regulation
  • beta-Arrestins

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