Targeting Fyn to Ameliorate Levodopa Induced Dyskinesia in the Mice Model of Parkinson´s Disease

BORDONE, MELINA P.; AVALE, ELENA; DAMIANICH, ANA; GERSHANIK, OSCAR S.; FERRARIO, JUAN E.; BERNARDI, ALEJANDRA

Miami

Congreso; 2018 MDS PanAmerican Congress; 2018

MDS

Objective: The management of levodopa induced dyskinesias (LID) in one of the greatest challenges in Parkinson?s disease (PD) research. We propose to genetically manipulate the kinase Fyn as a novel target to control LID.Background: Fyn is a key link between D1 and NMDA receptor. We have recently proposed it as a novel target to control LID and demonstrated that the Fyn inhibitor Saracatinib (AZD0530) is able to reduce LID in vivo (Sanz-Blasco et al 2017).Methods: We induced LIDs in a mice model of PD which were selected by observing spontaneous rotation and quantification of the cylinder test. Those animals with a remarked deficit of the contralateral forepaw in the cylinder test, were randomly assigned to receive intra-striatal injection of lentiviral particles carrying either a micro-RNA to knowdown Fyn (miR-Fyn) or a control sequence. Mice were challenged with L-DOPA to induce LID and the efficiency of the miR-Fyn were determined either to prevent or to revert already stablished dyskinesia. LIDs were determined every 3 days for 2 weeks. Postmortem, dopaminergic denervation was carefully determined to ensure an equal level of degeneration in all groups.Results: We found that the miR-Fyn we have designed is effective to reduce the amount of Fyn protein either in vitro or in vivo. Moreover, we determined that the local knowdown of Fyn in the striatum by means of the miR-Fyn is effective both to prevent and revert dyskinesias in mice.Conclusions: Our data demonstrate that Fyn is a potential target to control LID and a pre-clinical gene-therapy approach is effective to such goal. This results set the grounds for a potential translation of Fyn regulation to therapeutic use in PD.