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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1756969
- author
- 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
- organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Proceedings of the National Academy of Sciences
- volume
- 107
- pages
- 21824 - 21829
- publisher
- National Academy of 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
- 2016-04-04 08:41:05
- date last changed
- 2022-05-16 21:40:25
@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 Academy of 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}},
doi = {{10.1073/pnas.1012071107}},
volume = {{107}},
year = {{2010}},
}