title: 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.
abstract: 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.
authors: Division of Pharmacology, Department of Biomedical Sciences and Biotechnology and National Institute of Neuroscience, Italy. chiara.fiorentini@med.unibs.it
authors: Chiara
authors: C
authors: Fiorentini
authors: Paola
authors: P
authors: Savoia
authors: Daria
authors: D
authors: Savoldi
authors: Alessandro
authors: A
authors: Barbon
authors: Cristina
authors: C
authors: Missale
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D047468:Immunoprecipitation; D007980:Levodopa / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000378:metabolism*
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D017447:Receptors, Dopamine D1; D007980:Levodopa; D016627:Oxidopamine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11