Addressing a new target for L-DOPA induced dyskinesias

SANZ-BLASCO, SARA; DAMIANICH, ANA; SABORIDO, MARIANO; GOMEZ, GIMENA; BORDONE, MELINA; BERNARDI, ALEJANDRA; CAMPANA, SOLEDAD; TARAVINI, IRENE; HANGER, DIANE; AVALE, MARIA ELENA; GERSHANIK, OSCAR; FERRARIO, JUAN ESTEBAN

Chicago

Congreso; Neuroscience 2015; 2015

Society for Neuroscience

Symptomatic treatment with the dopamine precursor L-DOPA is at present the most effective therapy for the treatment of Parkinson?s disease (PD); however, its long-term administration frequently induces L-DOPA induced dyskinesias (LID). Dyskinesias are a priority within the scientific community because of their impact on the quality of life of PD patients, but the molecular mechanisms underlying L-DOPA-induced dyskinesias are not yet completely understood.Previous results from our lab show that the pleiotrophin receptor, RPTP-z/b is upregulated after L-DOPA treatment in a rodent model of PD. This receptor interacts with PSD95 and regulates the tyrosine kinase Fyn in the postsynaptic density complex. Fyn has been associated with learning, memory and long-term potentiation through the regulation of the NMDA receptor subunits NR2A and NR2B. After dopamine depletion and L-DOPA treatment, Fyn has been found to participate in NMDA receptors redistribution. In addressing Fyn as an intermediate in the development and maintenance of LID, and therefore as a potential novel target for the treatment of LID in PD, we have obtained the following results in our model of rodents with unilateral 6-OHDA lesion: after L-DOPA treatment, the number of pleiotrophin immunopositive striatal neurons and the phosphorilation level of Fyn is increased in dyskinetic rats. In addition, LIDs are reduced in both intensity and duration in Fyn KO mice compared to WT ones with equivalent lesion severity as demonstrated by TH inmunohistochemistry and behavioral tests. Our results show that the kinase Fyn appears to have an important role in LID, highlighting this protein as a novel target of study for the treatment of this side effect of L-DOPA therapy.