Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia.

Emanuela Santini (1) , Veronique Sgambato-Faure (2) , Qin Li (3, 4) , Marc Savasta (5) , Sandra Dovero (4) , Gilberto Fisone (1) , Erwan Bezard (3, 4)

1 Departement Neurosciences
2 ISC-MJ - Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229
3 Institute of Lab Animal Sciences
4 MAC - Laboratoire Mouvement Adaptation Cognition
5 INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement

BACKGROUND: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP - protein kinase A and of the Ras-extracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. METHODOLOGY/RESULTS: We here studied, in the gold-standard non-human primate model of Parkinson's disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. CONCLUSION: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure. While cAMP signalling enhancement is associated with dyskinesia, abnormal ERK signalling is associated with priming.

Domaines: Biochimie, Biologie Moléculaire

Emanuela Santini, Veronique Sgambato-Faure, Qin Li, Marc Savasta, Sandra Dovero, et al.. Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia.. PLoS ONE, 2010, 5 (8), pp.e12322. ⟨10.1371/journal.pone.0012322⟩. ⟨inserm-00628011⟩