An innovative approach to treat levodopa-induced dyskinesia based on targeting striatal intracellular signalling. Ente finanziatore Fondazione S. Paolo

(i) State of the art Parkinson’s disease (PD) is a neurodegenerative disorders characterised by progressive loss of dopamine innervation in the striatum. While Levodopa (L-DOPA) remains the gold standard of symptomatic therapy of PD it also causes severe long-term sideeffects in the form of involuntary movements (L-DOPA-induced dyskinesia, LID). The cellular and molecular mechanisms of LID formation and maintenance have started to be elucidated. Among the cellular adaptations occurring in the striatum, the brain region mainly affected in PD and LID patients, overactivation of dopamine D1 receptors, glutamate receptors and their downstream cell signalling play a central role. (ii) Objective and rationale In this project we propose to target two key integrators of dopaminergic and glutamatergic inputs, namely Ras-GRF1 and DARPP-32, that regulate Ras-ERK signalling pathway in experimental rodent models of LID. (iii) Experimental Plan Lentiviral vector (LV) mediated expression of either small harpin RNAs (shRNAs) specific for Ras-GRF1 and DARPP-32 or dominant negative constructs for Ras-GRF1 will be injected in the dorsal portion of striatum. The different and complementary expertise provided by the four partners in the project will allow us to investigate at the behavioural, cellular, electrophysiological, neurochemical and morphological level the potential therapeutic antidyskinetic action of this novel genetic approach. (iv) Expected results and their relevance We expect to block the Ras-ERK pathway and prevent LID development (priming) and maintenance. We hopefully will demonstrate that modulation of Ras-GRF1 and/or DARPP-32 activity represents a valid therapeutic approach for devising a still lacking effective treatment for LID