Dissecting the molecular mechanisms of Fynmediated levodopa induced dyskinesias

MELINA BORDONE; SARA SANZ BLASCO; OSCAR GERSHANIK; ALEJANDRA BERNARDI; GIMENA GOMEZ; JUAN E FERRARIO; ANA DAMIANICH; MARIA ELENA AVALE

Berlin

Congreso; 20th International Congress on Parkinson's Disease -Movement Disorders Society; 2016

Movement Disorders Society

Objective: To investigate the crosstalk between D1 receptor (D1R) and the signaling of Fyn protein kinase ina mice model of levodopa (L-DOPA) induced dyskinesias (LID).Background: In order to control the development of LID in PD therapy it is necessary to deeply understandthe multiple cellular and molecular changes that take place in the striatum. Plenty of evidence have linked theupregulation of D1R signaling and LID expression. We have previously explored the pathwayPleiotrophin/RPTPζ/b/Fyn, which is altered as a consequence of dopaminergic cell loss and L-DOPA treatment. RPTPζ/b interacts with PSD95 at the postsynaptic density complex and regulates Fyn, a key molecule involved in synaptic plasticity and cytoskeleton stability. We have already demonstrated a signiÖcant increase in the amount of phosphorylated Fyn protein in the striatum of dyskinetic animals.Methods: We reproduced the model of LID both in Fyn knock-out (KO) and wild type (WT) mice. Dopaminergic Öbers were damaged with unilateral injection of 6-OHDA and mice were treated with daily doses of L-DOPA for 2 weeks (6-OHDA+L-DOPA). Additional experimental groups were used as control for surgery (sham+vehicle), treatment (sham+L-DOPA) and lesion (6-OHDA+vehicle). We performed behavioral tests to determine abnormal involuntary movements (AIMs). Dopaminergic denervation was conÖrmed by immunodetection of TH in the SNpc. Molecular markers of LID, TH and other proteins were determined by Western blot.Results: As previously reported, Fyn-KO mice displayed lower levels of AIMs than WT littermates. Here we compared the amount and/or state of phosphorylation of several proteins related with D1R and the Fyn cascade, such as Fyn, Tau, FosB/ΔFosB, ERK and p70S6K, both in WT and Fyn-KO mice striata. We have reproduced previously reported changes in the regulation of several LID markers on WT mice while the regulation of some of these proteins in Fyn-KO mice was signiÖcantly altered.Conclusions: The lower level of LIDs in Fyn-KO mice appears to be associated to a downregulation of the transcription factor ΔFosB. Other candidate molecules are under further analysis to unravel the mechanism by which Fyn participates in the development of dyskinesias.