Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson’s disease.
Proc Natl Acad Sci USA. 2015-04-27; 112(19): E2517-E2526
DOI: 10.1073/pnas.1502740112
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1. Proc Natl Acad Sci U S A. 2015 May 12;112(19):E2517-26. doi:
10.1073/pnas.1502740112. Epub 2015 Apr 27.
Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in
Parkinson’s disease.
Urs NM(1), Bido S(2), Peterson SM(3), Daigle TL(3), Bass CE(4), Gainetdinov
RR(5), Bezard E(2), Caron MG(6).
Author information:
(1)Departments of Cell Biology, .
(2)Institut des Maladies Neurodégénératives, UMR 5293, Université de Bordeaux,
33000 Bordeaux, France; Institut des Maladies Neurodégénératives, UMR 5293, CNRS,
33000 Bordeaux, France;
(3)Departments of Cell Biology.
(4)Department of Pharmacology and Toxicology, University at Buffalo, The State
Uiversity of New York, Buffalo, NY 14260; and.
(5)Departments of Cell Biology, Institute of Translational Biomedicine, St.
Petersburg State University, St. Petersburg, 199034, Russia.
(6)Departments of Cell Biology, Medicine, and Neurobiology, Duke University
Medical Center, Durham NC 27710; .
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.
DOI: 10.1073/pnas.1502740112
PMCID: PMC4434696
PMID: 25918399 [Indexed for MEDLINE]