Journal
MOVEMENT DISORDERS
Volume 31, Issue 4, Pages 512-520Publisher
WILEY-BLACKWELL
DOI: 10.1002/mds.26581
Keywords
l-dopa-induced dyskinesia; Shp-2; Erk1; 2; dopamine D1 receptor; shRNA silencing
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BackgroundDyskinesia, 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. ObjectivesIn 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. MethodsLentiviral 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. ResultsThe 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. ConclusionThese data suggest that the striatal D1 receptor/Shp-2 complex may represent a promising novel target for the development of antidyskinetic drugs. (c) 2016 International Parkinson and Movement Disorder Society
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