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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; Bezard, Erwan; D'Antoni, Angela; Francardo, Veronica LU ; Indrigo, Marzia; Qin, Li; Doveró, Sandra; Cerovic, Milica; Cenci Nilsson, Angela LU and Brambilla, Riccardo (2010) In Proceedings of the National Academy of Sciences 107. p.21824-21829
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... (More)
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. (Less)
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Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
107
pages
21824 - 21829
publisher
National Acad Sciences
external identifiers
  • wos:000285521500107
  • pmid:21115823
  • scopus:78650753240
ISSN
1091-6490
DOI
10.1073/pnas.1012071107
language
English
LU publication?
yes
id
5e8b356a-c3c7-4e62-b3fe-2aed386fe268 (old id 1756969)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21115823?dopt=Abstract
date added to LUP
2011-01-03 09:46:11
date last changed
2018-07-15 04:19:38
@article{5e8b356a-c3c7-4e62-b3fe-2aed386fe268,
  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.},
  author       = {Fasano, Stefania and Bezard, Erwan and D'Antoni, Angela and Francardo, Veronica and Indrigo, Marzia and Qin, Li and Doveró, Sandra and Cerovic, Milica and Cenci Nilsson, Angela and Brambilla, Riccardo},
  issn         = {1091-6490},
  language     = {eng},
  pages        = {21824--21829},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia.},
  url          = {http://dx.doi.org/10.1073/pnas.1012071107},
  volume       = {107},
  year         = {2010},
}