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

Fasano, Stefania ORCID: https://orcid.org/0000-0002-3696-7139, Bezard, E., D'Antoni, A., Francardo, V., Indrigo, M., Qin, L., Dovero, S., Cerovic, Milica, Cenci, M. A. and Brambilla, Riccardo ORCID: https://orcid.org/0000-0003-3569-5706 2010. Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia. Proceedings of the National Academy of Sciences 107 (50) , pp. 21824-21829. 10.1073/pnas.1012071107

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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, 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Publisher:	The National Academy of Sciences of the USA
ISSN:	0027-8424
Last Modified:	05 Nov 2022 15:06
URI:	https://orca.cardiff.ac.uk/id/eprint/22376

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