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Stefania Fasano"Inhibition of Ras-GRF1 and ERK signalling in the striatum reverts motor symptoms associated to L-DOPA induced Dyskinesia"

Abstract :

L-DOPA induced dyskinesia (LID) is a common complication of the pharmacotherapy in Parkinson's disease (PD) that can be modelled in rodents by monitoring abnormal involuntary movements (AIMs). Recent evidence suggests that LID formation may be causally linked to abnormal cellular adaptations in the basal ganglia, including supersensitivity to dopamine in the striatum. Amongst the best characterised cell signalling pathways downstream to dopamine D1-receptors lies the Ras-ERK cascade. This pathway controls both cytosolic and nuclear changes in the brain and has already been demonstrated to be hyperactivated in the dopamine depleted striata treated with L-DOPA. To further determine whether brain specific components of the Ras-ERK pathway may become molecular targets for treating LID, we have investigated in genetically modified mice the potential role of Ras-GRF1, a specific activator of the Ras small GTPases in neuronal cells of the central nervous system using a well established 6-hydroxydopamine (6-OHDA) mouse model of PD. In particular, Ras-GRF1 knockout (Ras-GRF1 KO) and wild-type mice received a unilateral injection of the neurotoxin 6-OHDA into the medial forebrain bundle and, following two weeks of recovery, were then given increasing doses of L-DOPA for 9 days. We analyzed the extent of the lesion and found a comparable degree of DA denervation in both Ras-GRF1 KO and wild-type mice indicating that PD-like motor deficits can be readily induced in these mice. However, following an escalating dose regimen of L-DOPA treatment, we found that Ras-GRF1 KO animals were significantly resistant to the development of AIMs. Consistently, we found that ERK activation and FosB/ΔFosB induction were markedly reduced in the striatum of Ras-GRF1 KO animals. Furthermore, to find a therapeutic tool for curtailing LID we have generated Lentiviral Vectors (LV) expressing dominant negative forms of Ras-GRF1. These viruses were injected in the striatum of dyskinetic non-human primates (NHP) previously rendered Parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) followed by chronic oral treatment with L-DOPA. 4 weeks after LVs injections we observed a dramatic reversion of the diskinetic profile in this NHP model of LID.
These data not only confirm the crucial requirement of the Ras-ERK pathway in LID formation but also demonstrate a central role of Ras-GRF1 in governing critical aspects associated to dopamine-dependent adaptations in the striatum.

Selected publications

Fasano, S., Pittenger C., and Brambilla, R.
Inhibition of CREB in the dorsal portion of the striatum causes reduced behavioural responses to cocaine and morphine. Inhibition of CREB activity in the dorsal portion of the striatum potentiates behavioral responses to drugs of abuse. Frontiers in Behavioural Neuroscience. (2009)
S. Fasano, A. D’Antoni, P. C. Orban, E. Valjent, E. Putignano, H. Vara, T. Pizzorusso, M. Giustetto, Y. Bongjune, M. P. Soloway, R. Maldonado, J. Caboche and R. Brambilla.Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) Controls Activation of Extracellular Signal-Regulated Kinase (ERK) Signaling in the Striatum and Long-Term Behavioral Responses to Cocaine. Biol Psychiatry. 2009 May 15.
Givogri MI, Bottai D, Zhu HL, Fasano S, Lamorte G, Brambilla R, Vescovi A, Wrabetz L, Bongarzone E. Multipotential neural precursors transplanted into the metachromatic leukodystrophy brain fail to generate oligodendrocytes but contribute to limit brain dysfunction. Dev Neurosci. 2008;30(5):340-57. Epub 2008 Jul 30