Exploring Fyn as a novel molecule in Levodopa induced dyskinesias

SANZ BLASCO S; AVALE E; CAMPANA S; SABORIDO M; GOMEZ G; TARAVINI I; GERSHANIK OS; FERRARIO JE

San Diego

Congreso; 19th International Congress of Parkinson?s Disease and Movement Disorders; 2015

International Parkinson and Movement Disorder Society

 Objective: To determine the role of the kinase Fyn in levodopainduced dyskinesias.Background: The administration of L-DOPA is the most effectivesymptomatic pharmacological therapy for Parkinson?s disease(PD). Despite its benefits, most patients develop side effects knownas L-DOPA induced dyskinesias (LID). One of the current greatchallenges in PD therapy is to control LID. To reach this goal it is necessary to better understand the multiple cellular and molecularmechanisms that take place during LID. Although some protein andgene changes have been described within the dyskinetic striatum, thefunctions and/or mechanism in which they are involved are not fullyunderstood. In our laboratory we have shown that Pleiotrophin andits receptor RPTPz/b are upregulated as a consequence of dopaminergiccell loss and L-DOPA treatment. RPTPz/b belongs to the postsynaptic density complex, where it interacts with PSD95 and regulatesthe protein kinase Fyn, a key molecule in postsynaptic signalingand reorganization. Several evidences suggest Fyn as a potential candidateinvolved in LID.Methods: We have determined the amount of Pleiotrophin immunopositiveneurons and analyzed the amount of Fyn protein and itsphosphorylation state by western blot in striata of dyskinetic rats.Also, we have developed the model of LID in both Fyn knock-out(KO) and WT mice, in which we have performed behavioral tests,determined abnormal involuntary movements (AIMs) and performedhistological determinations such as tyrosine hydroxylase and FosB/DFosB.Results: We found that the number of PTN positive neurons isincreased and that Fyn is highly phosphorylated in the striatum ofdyskinetic rats, while Fyn KO mice show a significant reduction inthe development of AIMs in comparison to WT controls.Conclusions: Our data suggest that Fyn might be involved in thedevelopment of LID, yet further work is still necessary to determinethe mechanism in which it may be involved and if it could be targetedto control LID.