Persistent activation of the D1R/Shp-2/Erk1/2 pathway in l-DOPA-induced dyskinesia in the 6-hydroxy-dopamine rat model of Parkinson's disease

Prolonged l-3,4-dihydroxyphenylalanine (l-DOPA) administration, the gold standard therapy for Parkinson's disease (PD) is associated with serious motor complications, known as l-DOPA-induced dyskinesia (LID). One of the major molecular changes associated with LID is the increased activity of the extracellular signal-regulated kinases 1/2 (Erk1/2) signaling in the medium spiny neurons of the striatum induced by malfunctioning in the dopamine D1 receptor (D1R)-mediated transmission.We have previously established that in the striatum, activation of Shp-2, an intracellular tyrosine phosphatase associated with the D1R, is a requisite for the D1R to activate Erk1/2.In this study, we investigated the role of striatal D1R/Shp-2 complex in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD.We found that in hemiparkinsonian rats experiencing LID, the physiological interaction between D1R and Shp-2 in the striatum was preserved. In these animals, the chronic activation of D1R either by l-DOPA or by the selective D1R agonist SKF 38393 induced both dyskinesia and Shp-2/Erk1/2 activation. These effects were prevented by the selective D1R-antagonist SCH23390 suggesting the involvement of striatal D1R/Shp-2 complex, via Erk1/2 activation, in the molecular events underlying LID. Interestingly, we found that D1R-mediated Shp-2-Erk1/2 activation was persistently detected in the striatum of dyskinetic rats during l-DOPA washout, with a close correlation between LID severity and the extent of long term activation of both Shp-2 and Erk1/2.Taken together, our data show that in hemiparkinsonian rats developing dyskinesia, the aberrant phosphorylation of Shp-2 by D1R activation, represents an upstream molecular event leading to the persistent phosphorylation of Erk1/2 and therefore a novel therapeutic target to counteract LID development and maintenance during l-DOPA therapy.

► Activation of Shp-2 is a requisite event for the D1R to activate striatal Erk1/2. ► Erk1/2 phosphorylation and LID development requires the D1R/Shp-2 complex activation. ► In dyskinetic rats, Shp-2/Erk1/2 activation is persistent during l-DOPA withdrawal. ► Long lasting Shp-2/Erk1/2 activation correlates with the severity of LID.