RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease

Stephen J. Gold, Chau V. Hoang, Bryan W. Potts, Gregory Porras, Elsa Pioli, Woo Kim Ki, Agnes Nadjar, Chuan Qin, Gerald J. LaHoste, Qin Li, Bernard H. Bioulac, Jeffrey L. Waugh, Eugenia Gurevich, Rachael L. Neve, Erwan Bezard

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102 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)14338-14348
Number of pages11
JournalJournal of Neuroscience
Volume27
Issue number52
DOIs
Publication statusPublished - 2007 Dec 26

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Gold, S. J., Hoang, C. V., Potts, B. W., Porras, G., Pioli, E., Ki, W. K., Nadjar, A., Qin, C., LaHoste, G. J., Li, Q., Bioulac, B. H., Waugh, J. L., Gurevich, E., Neve, R. L., & Bezard, E. (2007). RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease. Journal of Neuroscience, 27(52), 14338-14348. https://doi.org/10.1523/JNEUROSCI.4223-07.2007