Levodopa is the most effective drug for the treatment of Parkinson's disease (PD). However, the long-term use of this dopamine (DA) precursor is complicated by highly disabling dyskinesia. Although clinical findings suggested that pulsatile stimulation of DA receptors is an important mechanism in levodopa-induced dyskinesias (LIDs), LIDs pathogenesis is still unclear. In animal models, loss of downscaling at cortico-striatal synapses and abnormal activity of a molecular cascade downstream the activation of DA D1 and N-methyl-D-aspartate (NMDA) glutamate receptors are key features of LIDs.

Despite this knowledge achievement, pharmacological prevention of dyskinetic movements is still an unmet need. Thus, the main goal of this project is to use a translational approach to identify the molecular profile of patient?s biofluids presenting high risk to develop LIDs for a targeted pharmacological approach. Preliminary findings suggest that a reduced level of total alpha-synuclein (a-syn) in the cerebrospinal fluid (CSF) of PD patients in the early stage, possibly reflecting an increased cerebral accumulation, is predictive of an earlier development of LIDs. Growing evidence in the last few years suggested a functional/pathological interaction between a-syn and leucine-rich repeat kinase 2 (LRRK2). Interestingly, very recent data clearly show that pharmacological inhibition of LRRK2 worsens the dyskinetic motor behaviour in 6-hydroxydopamine (6-OHDA) rat model of LIDs. Thus, a biochemical and genetic study will be conducted to evaluate whether changes of a-syn and LRRK, two key proteins involved in PD pathogenesis, may predict the development of LIDs.

The potential role of a-syn and LRRK2 and their interaction with the nigro-striatal transmission will be investigated in the pathogenesis of LIDs. As regards a-syn a molecular modelling approach will be used to identify relevant target surfaces potentially suitable for a high-throughput screening (HTS) approach. In particular, we aim at identifying novel compounds able to uncouple Rabphilin3A (Rph3A)-a-syn complex, for pharmacological purposes. The mechanisms by which the a-syn aggregation and LRRK2 phosphorylation states predict LIDs occurrence will be studied by a multidisciplinary approach using in vivo intra-cerebral overexpression of AAV-a-syn and LRRK KO rodent models respectively. The obtained findings will allow identifying CSF profiles guiding the rational use of the existing pharmacological armamentarium and the design of tailored pharmacological novel strategies to control this disabling neurological condition.

Partner:

1. Università Cattolica del Sacro Cuore (Coordinator);
2. Università degli Studi di Perugia; 
3. Università degli Studi di Milano;
4. Consiglio Nazionale delle Ricerche;
5. Università degli Studi di Roma “Tor Vergata”;
6. Università Telematica San Raffaele Roma;
7. Università degli Studi di Trento.