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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.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 12/14/2010, Vol. 107 Issue 50, p21824-21829. 6p. 1 Color Photograph, 3 Graphs. - Publication Year :
- 2010
-
Abstract
- i-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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CATECHOLAMINES
*BRAIN diseases
*BIOGENIC amines
*AMINES
*DOBUTAMINE
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 107
- Issue :
- 50
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 59617812
- Full Text :
- https://doi.org/10.1073/pnas.1012071107