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 receptormediated 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-dopainduced dyskinesia development was investigated by in vivo silencing of Shp-2 in the striatum of the 6-hydroxydopamine 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.
Shp-2 knockdown prevents l-dopa-induced dyskinesia in a rat model of Parkinson's disease
Fiorentini, Chiara;Savoia, Paola;Savoldi, Daria;Bono, Federica;Busi, Chiara;Barbon, Alessandro;Missale, Mariacristina
2016-01-01
Abstract
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 receptormediated 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-dopainduced dyskinesia development was investigated by in vivo silencing of Shp-2 in the striatum of the 6-hydroxydopamine 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
