Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease.
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.
Departments of Cell Biology, marc.caron@dm.duke.edu nikhil.urs@duke.edu.
Nikhil M
NM
Urs
Institut des Maladies Neurodégénératives, UMR 5293, Université de Bordeaux, 33000 Bordeaux, France; Institut des Maladies Neurodégénératives, UMR 5293, CNRS, 33000 Bordeaux, France;
Simone
S
Bido
Departments of Cell Biology.
Sean M
SM
Peterson
Departments of Cell Biology.
Tanya L
TL
Daigle
Department of Pharmacology and Toxicology, University at Buffalo, The State Uiversity of New York, Buffalo, NY 14260; and.
Caroline E
CE
Bass
Departments of Cell Biology, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, 199034, Russia.
Raul R
RR
Gainetdinov
Institut des Maladies Neurodégénératives, UMR 5293, Université de Bordeaux, 33000 Bordeaux, France; Institut des Maladies Neurodégénératives, UMR 5293, CNRS, 33000 Bordeaux, France;
Erwan
E
Bezard
Departments of Cell Biology, Medicine, and Neurobiology, Duke University Medical Center, Durham NC 27710; marc.caron@dm.duke.edu nikhil.urs@duke.edu.
Marc G
MG
Caron
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000737:chemistry; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism; D020820:Dyskinesias / Q000378:metabolism*; D017353:Gene Deletion; D007980:Levodopa / Q000737:chemistry*; D008251:Macaca; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine / Q000737:chemistry; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015854:Up-Regulation; D000071557:beta-Arrestins
D019390:Arrestins; D000071557:beta-Arrestins; D007980:Levodopa; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine
beta-arrestin; biased signaling; dopamine receptors; dyskinesia; l-DOPA