Dissecting the molecular mechanisms of Fyn-mediated levodopa induced dyskinesias

BORDONE M; BERNARDI MA; DAMIANICH A; SANZ BLASCO S; GOMEZ G; TARAVINI I; AVALE E; GERSHANIK OS; FERRARIO JE

Berlín

Congreso; 20th International Congress of Parkinson's Disease and Movement Disorders; 2016

International Parkinson and Movement Disorder Society

Objective: To investigate the crosstalk between D1 receptor (D1R)and the signaling of Fyn protein kinase in a mice model of levodopa (L-DOPA)induced dyskinesias (LID).Background: In order to control the development of LID in PD therapyit is necessary to deeply understand the multiple cellular and molecularchanges that take place in the striatum. Plenty of evidence have linkedthe upregulation of D1R signaling and LID expression. We have previouslyexplored the pathway Pleiotrophin/RPTPf/b/Fyn, which is altered asa consequence of dopaminergic cell loss and L-DOPA treatment. RPTPf/binteracts with PSD95 at the postsynaptic density complex and regulatesFyn, a key molecule involved in synaptic plasticity and cytoskeleton stability.We have already demonstrated a significant increase in the amountof 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 fibers were damagedwith unilateral injection of 6-OHDA and mice were treated with dailydoses of L-DOPA for 2 weeks (6-OHDA1L-DOPA). Additional experimentalgroups were used as control for surgery (sham1vehicle), treatment(sham1L-DOPA) and lesion (6-OHDA1vehicle). We performedbehavioral tests to determine abnormal involuntary movements (AIMs).Dopaminergic denervation was confirmed by immunodetection of TH inthe SNpc. Molecular markers of LID, TH and other proteins were determinedby Western blot.Results: As previously reported, Fyn-KO mice displayed lower levelsof AIMs than WT littermates. Here we compared the amount and/or stateof phosphorylation of several proteins related with D1R and the Fyn cascade,such as Fyn, Tau, FosB/DFosB, ERK and p70S6K, both in WT andFyn-KO mice striata. We have reproduced previously reported changes inthe regulation of several LID markers on WT mice while the regulation ofsome of these proteins in Fyn-KO mice was significantly altered.Conclusions: The lower level of LIDs in Fyn-KO mice appears to beassociated to a downregulation of the transcription factor DFosB. Othercandidate molecules are under further analysis to unravel the mechanismby which Fyn participates in the development of dyskinesias.