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. 2010-11-29; 107(50): 21824-21829
DOI: 10.1073/pnas.1012071107
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1. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21824-9. doi:
10.1073/pnas.1012071107. Epub 2010 Nov 29.
Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in
the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia.
Fasano S(1), Bezard E, D’Antoni A, Francardo V, Indrigo M, Qin L, Doveró S,
Cerovic M, Cenci MA, Brambilla R.
Author information:
(1)Basal Ganglia Pathophysiology Unit, Department of Experimental Medical
Science, Lund University, BMC F11, Lund 221 84, Sweden.
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.
DOI: 10.1073/pnas.1012071107
PMCID: PMC3003069
PMID: 21115823 [Indexed for MEDLINE]