Ph.D. Projects


The role of Ras-GRF1/2 and the ERK signalling pathway in motor and cognitive dysfunctions associated to L-DOPA induced Dyskinesia and Parkinson’s Disease

Poorly understood cellular adaptations in the striatum are involved in the long-term side effects and reduced efficacy of current pharmacotherapy of Parkinson’s Disease (PD), such as L-DOPA treatment. We and others have recently shown that alterations in the Ras-ERK signalling pathway in the dorsal striatum are relevant to L-DOPA induced Dyskinesia (LID), a disease occurring within 5 years in the large majority of treated PD patients. This project will evaluate the role of Ras-GRF1 and Ras-GRF2, two brain specific-activators of the Ras-ERK pathway, in the development of LID. Both classical gene targeted mouse mutants (Ras-GRF1 knock out and overexpressing animals) and lentiviral vectors expressing either signalling mutants or causing RNA interference will be tested at the behavioural level, also upon L-DOPA treatment. Moreover, in collaboration with Dr. S. Pluchino, neuro progenitor cells (NPCs) manipulated in order to express Ras-GRF1/2 and ERK inhibitory peptides will be injected in the dorsal portion of the striatum, with the aim to provide initial evidence for a cell-based therapy of LID. These experiments will confirm whether the modulation of Ras-ERK signalling in striatum by Ras-GRF1/2 manipulations might serve as an effective treatment for LID, by attenuating the development of motor and cognitive complications associated to the current pharmacotherapy of PD.