Shp-2 knockdown prevents l-dopa-induced dyskinesia in a rat model of Parkinson's disease

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.