title: Shp-2 knockdown prevents l-dopa-induced dyskinesia in a rat model of Parkinson's disease.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  These data suggest that the striatal D1 receptor/Shp-2 complex may represent a promising novel target for the development of antidyskinetic drugs.
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorentini
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Savoia
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Savoldi
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Bono
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Busi
authors.affiliation: Section of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barbon
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000517:prevention & control; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Erk1/2; Shp-2; dopamine D1 receptor; l-dopa-induced dyskinesia; shRNA silencing