PNR2B mediates the role of FYN kinase in levodopa induced dyskinesia in a mouse model of Parkinson's disease

M BORDONE; L ISAJA; SANZ BLASCO S; A DAMIANICH; E AVALE; O GERSHANIK; J FERRARIO

Paris

Congreso; ISN-ESN Meeting; 2017

International Society for Neurochemistry (ISN)

Levodopa (L-DOPA) induced dyskinesia (LID) is one of theundesired side effects of Parkinson?s dis ease (PD) treat ment. Tore duce the de velop ment of LID, without affecting the positiverestorative effect of dopamine stimulation, is one of the greatestchallenge in this area. We have pre viously explored the pathwayPleiotrophin/RPTP ζ/b/Fyn at the post synaptic density com plexand found that Fyn-KO mice de velop ed less LID than WTlittermates. Fyn kinase modulates the N-methyl D-aspartate(NMDA) receptor through phos phorylation of the NR2B subunitand this could explain the role of Fyn in LID. The main goal ofthis work is to demon strate the direct relation be tween Fyn andNMDA receptor in a para digm of dyskinesia. We lesioned Fyn-KOand WT mice with 6-hydroxy dopamine (6-OHDA) and treatedthem daily with L-DOPA to model LID. Postmortem dopaminergicdenervation was confirmed by immuno detection of tyrosinehydroxy lase in the sub stanti a nigra pars com pacta. Several molecularmarkers, in particular the amount and phos phorylation statusof NR2B subunit of NMDA, were determined in the striatum byWestern blot. As expected, in WT mice we found upre gulated thetrans cription factor ΔFosB and ERK phos phorylation, both previouslyreported markers of LID, while Fyn-KO mice showed asig nifi cant re duction of LID accom panied by a down regu lation ofΔFosB and NR2B phos phorylation (pNR2B). In conclusion,pNR2B is down regu lated in dyskinetic Fyn-KO mice, what canexplain a re duced NMDA sig nal ing and there fore the ob served reduceddyskinesia. In this sense, Fyn would be an attractive targetto modify the NMDA sig nal ing and a pro mising treat ment tomodulate LID without affecting the thera peutic efficacy of LDOPAin PD.