JCJC - Jeunes chercheuses & jeunes chercheurs

Targeting the RAS-MAPK Signalling Pathway for treating movement disorders – MAPKinDysk

Submission summary

Levodopa-induced dyskinesia (LID) represent a debilitating complication of levodopa therapy for Parkinson's disease (PD), which underlying neural mechanisms are far from clear although major advances have been made in recent years. Once LID have appeared, they can be persistently triggered by a single dose of levodopa, even after several weeks of washout. Several studies indicate that persistent changes in striatal expression of selected neurotransmitter-related genes are critical for the development of LID. We recently accumulated experimental evidences suggesting that the plastic phenomena are limited to single striatal neurons (no reorganization of the network) that do not change fundamentally their basic neurotransmitter phenotype, but which transcriptional machinery is dramatically affected during the course of long-term levodopa treatment, i.e. paving the way for understanding the mechanisms of the priming phenomenon. We posit that the priming phenomenon is caused by a patterned activation of the mitogen-activated protein kinase (MAPK) signalling cascade, and especially the Ras-extracellular signal-regulated kinases (Ras-ERK). Our project will thus focus on the study of the Ras-ERK pathway in the non-human primate model of LID according to 4 specific aims (SA). SA1 aims at defining the steady-state levels of MAPK-signalling cascade proteins in the most comprehensive experimental population of non-human primates: normal treated with vehicle, normal treated only once with levodopa, normal chronically treated with L-dopa, parkinsonian, parkinsonian treated only once with levodopa, parkinsonian chronically treated with levodopa without exhibiting dyskinesia and parkinsonian chronically treated with levodopa and exhibiting overt dyskinesia. Such design will allow to distinguish the effects caused by the lesion from those caused by the treatment. SA2 aims at defining the anatomo-functional pattern of Ras-ERK activation in the same conditions by precising the role of the different cortico-basal ganglia-thalamus relays in thoese changes while SA3 aims at identifying the neurochemical identity and projections of the striatal neurons expressing changes in ras-ERK levels. Since final evidence for a role in priming and/or in behavioural expression or maintenance of LID should be obtained through modulation of the MAPK cascade activity, we would develop proof-of-concept therapeutic approaches based on lentiviral gene transfer technology (SA4). The goal will therefore be to interfere with RasGRF1 activity, the neuronal and striatum-enriched specific activator of Ras proteins, in the striatum of parkinsonian (MPTP-lesioned) non-human primates. We would therefore monitor the motor behaviour of drug-naïve (non-primed) (SA 4.3) and levodopa-treated (primed) (SA 4.4) animals after intrastrial stereotactic injection of (i) lentiviral vector-mediated expression of RasGRF1 gene and (ii) lentiviral vector-mediated expression of RasGRF1 dominant negative gene. The vectors will have previously been prepared by R. Brambilla (Milano, Italy - SA 4.1) and validated in a pilot experiment in primates (SA 4.2). Thus, after completion of these experiments, we will possibly have a potential therapeutic strategy for preventing appearance of LID (cancelling priming) and/or for disrupting the maintenance of priming (indirect reduction in LID severity).

Project coordination

Erwan BEZARD (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 150,000 euros
Beginning and duration of the scientific project: - 36 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter