Background: Dyskinesia, the major side effect of l-dopa therapy in PD, is mainly associated with nonphysiological stimulation of denervated receptors in the striatum. In particular, DA D1 receptor-mediated aberrant extracellular signal-regulated protein kinases 1 and 2 activation have been associated with striatal changes leading to dyskinesia. We recently identified the tyrosine phosphatase Shp-2 as a crucial effector transmitting D1 receptor signaling to extracellular signal-regulated protein kinases 1 and 2 activation and reported the involvement of the D1 receptor/Shp-2/extracellular signal-regulated protein kinases 1 and 2 pathway in the development of l-dopa-induced dyskinesia.
Objectives: In this study, the role of Shp-2 in l-dopa-induced dyskinesia development was investigated by in vivo silencing of Shp-2 in the striatum of the 6-hydroxy-dopamine rat model of PD.
Methods: Lentiviral particles delivering short hairpin RNA were used to obtain long-term striatal Shp-2 downregulation. Rats were then treated with l-dopa and analyzed for both the improvement of akinesia and the development of l-dopa-induced dyskinesia.
Results: The results show that Shp-2 knockdown remarkably decreased extracellular signal-regulated protein kinases 1 and 2 phosphorylation and attenuated the severity of l-dopa-induced dyskinesia likely without compromising the therapeutic efficacy of l-dopa.
Conclusion: These data suggest that the striatal D1 receptor/Shp-2 complex may represent a promising novel target for the development of antidyskinetic drugs.
Keywords: Erk1/2; Shp-2; dopamine D1 receptor; l-dopa-induced dyskinesia; shRNA silencing.
© 2016 International Parkinson and Movement Disorder Society.