Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia.
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.
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, BMC F11, Lund 221 84, Sweden.
Stefania
S
Fasano
Erwan
E
Bezard
Angela
A
D'Antoni
Veronica
V
Francardo
Marzia
M
Indrigo
Li
L
Qin
Sandra
S
Doveró
Milica
M
Cerovic
M Angela
MA
Cenci
Riccardo
R
Brambilla
D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism*
D020666:ras-GRF1; D007980:Levodopa; D048049:Extracellular Signal-Regulated MAP Kinases