Ricerc@Sapienza

Levodopa-induced dyskinesia (LID) is a frequent complication of long-term treatment with L-DOPA in Parkinson's disease (PD) patients. Choreothetosic movements of LID are extremely disabling and limit significantly functionality and quality of life of advanced PD patients. Treatment of LID is rather unsatisfactory, being limited in the majority of cases to reduction of dopaminergic therapy, in turn causing worsening of parkinsonism.
The pathophysiology of LID in PD is rather complex. Preclinical and clinical studies point on excessive glutamate activity at level of cortical-subcortical frontostriatal motor circuitries. Excessive glutamate transmission may also contribute to neurotoxicity in PD. In the present study we will investigate the relationships between mGlu3 and mGlu5 receptor polymorphisms and LID in a large PD cohort (>1500 subjects). This will be coupled with preclinical investigations on the role of mGlu3 and mGlu5 receptors in neurotoxicity and LID in experimental models of PD (6-OHDA lesion in rats and MPTP lesion in mice).
This project will combine robust preclinical studies with up-to-date genomics investigation in PD patients. The results, therefore, will provide a complete scenario on the role of mGlu-mediated transmission in LID in PD, and improve current knowledge on the pathogenesis and treatment of LID in PD as well as on the feasibility of identifying by genomics assay subjects at risk of developing LID. These findings may prove useful for future strategies of prevention and treatment of LID, a currently unmet need for treatment of PD. In addition, the project will establish whether a drug that inhibits mGlu5 receptors and a drug that activates mGlu3 receptors act synergistically in protecting nigro-striatal neurons in a model of progressive degeneration occurring in PD. The identification of effective neuroprotective strategies is a further unmet need in the treatment of PD with potentially high impact for human societies.