RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease.
Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9-2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9-/- mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior--taken as an index of the anti-parkinsonian response--is similar between the two groups of mice. Together, these findings suggest that RGS9-2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9-2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.
Gold
Stephen J
SJ
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Hoang
Chau V
CV
Potts
Bryan W
BW
Porras
Gregory
G
Pioli
Elsa
E
Kim
Ki Woo
KW
Nadjar
Agnes
A
Qin
Chuan
C
LaHoste
Gerald J
GJ
Li
Qin
Q
Bioulac
Bernard H
BH
Waugh
Jeffrey L
JL
Gurevich
Eugenia
E
Neve
Rachael L
RL
Bezard
Erwan
E
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D004295:Dihydroxyphenylalanine / Q000009:adverse effects*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000009:adverse effects*; D020820:Dyskinesias / Q000209:etiology* / Q000503:physiopathology* / Q000628:therapy; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020267:MPTP Poisoning / Q000188:drug therapy; D008252:Macaca fascicularis; D051379:Mice; D018345:Mice, Knockout; D016627:Oxidopamine / Q000494:pharmacology; D020710:RGS Proteins / Q000008:administration & dosage / Q000378:metabolism*; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology*; D013565:Sympatholytics / Q000494:pharmacology
D015259:Dopamine Agents; D020710:RGS Proteins; D013565:Sympatholytics; C116925:regulator of g-protein signaling 9; D004295:Dihydroxyphenylalanine; D016627:Oxidopamine