Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia.
Författare
Summary, in English
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.
Avdelning/ar
Publiceringsår
2010
Språk
Engelska
Sidor
21824-21829
Publikation/Tidskrift/Serie
Proceedings of the National Academy of Sciences
Volym
107
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
National Academy of Sciences
Ämne
- Neurosciences
Status
Published
Forskningsgrupp
- Basal Ganglia Pathophysiology
ISBN/ISSN/Övrigt
- ISSN: 1091-6490