1. Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa--induced dyskinesia
- Author
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Fasano, Stefania, Bezard, Erwan, DAntoni, Angela, Francardo, Veronica, Indrigo, Marzia, Qin, Li, Dovero, Sandra, Cerovic, Milica, Cenci, M. Angela, and Brambilla, Riccardo
- Subjects
Dopa -- Research ,Dopa -- Care and treatment ,Movement disorders -- Research ,Movement disorders -- Care and treatment ,Guanine -- Research ,Guanine -- Properties ,Nucleotides -- Research ,Nucleotides -- Properties ,Corpus striatum -- Research ,Science and technology - Abstract
L-dopa-induced dyskinesia (LID) is a common debilitating complication of dopamine replacement therapy in Parkinson's disease. Recent evidence suggests that LID may be linked causally to a hyperactivation of the Ras-ERK signaling cascade in the basal ganglia. We set out to determine whether specific targeting of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a brain-specific activator of the Ras-ERK pathway, may provide a therapy for LID. On the rodent abnormal involuntary movements scale, RasGRF1-deficient mice were significantly resistant to the development of dyskinesia during chronic L-dopa treatment. Furthermore, in a nonhuman primate model of LID, lentiviral vectors expressing dominant negative forms of Ras-GRF1 caused a dramatic reversion of dyskinesia severity leaving intact the therapeutic effect of L-dopa. These data reveal the central role of Ras-GRF1 in governing striatal adaptations to dopamine replacement therapy and validate a viable treatment for LID based on intracellular signaling modulation. doi: 10.10731pnas.1012071107
- Published
- 2010