RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson’s disease.
Journal of Neuroscience. 2007-12-26; 27(52): 14338-14348
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1. J Neurosci. 2007 Dec 26;27(52):14338-48.
RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in
experimental Parkinson’s disease.
Gold SJ(1), Hoang CV, Potts BW, Porras G, Pioli E, Kim KW, Nadjar A, Qin C,
LaHoste GJ, Li Q, Bioulac BH, Waugh JL, Gurevich E, Neve RL, Bezard E.
(1)Department of Psychiatry, University of Texas Southwestern Medical Center at
Dallas, Dallas, Texas 75390, USA.
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.
PMID: 18160641 [Indexed for MEDLINE]