Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia.

Summary, in English

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, Ras-GRF1-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.

• Author: Stefania Fasano; Erwan Bezard; Angela D'Antoni; Veronica Francardo; Marzia Indrigo; Li Qin; Sandra Doveró; Milica Cerovic; Angela Cenci Nilsson; Riccardo Brambilla
• Department/s: Basal Ganglia Pathophysiology; MultiPark: Multidisciplinary research focused on Parkinson´s disease
• Publishing year: 2010
• Language: English
• Pages: 21824-21829
• Publication/Series: Proceedings of the National Academy of Sciences
• Volume: 107
• Links: http://www.ncbi.nlm.nih.gov/pubmed/21115823?dopt=Abstract; http://dx.doi.org/10.1073/pnas.1012071107
• Document type: Journal article
• Publisher: National Academy of Sciences
• Topic: Neurosciences
• Status: Published
• Research group: Basal Ganglia Pathophysiology
• ISBN/ISSN/Other: ISSN: 1091-6490