Targeting NR2A-containing NMDA receptors in striatal postsynaptic membranes in early stages of Parkinson's Disease and in L-DOPA induced dyskinesia

Understanding the molecular components guiding the correct assembly of the glutamatergic synapse is a challenge in the comprehension of the mechanisms regulating synaptic strength in physiological and pathological conditions. Indeed, the localization of ionotropic glutamate receptors, NMDA-type, in the postsynaptic density modulates the response of the postsynaptic neuron to different stimuli, both in activity-dependent synaptic plasticity and in neurodegenerative disorders. Our groups have described the role of NMDA receptor synaptic localization and interaction with PSD-MAGUK family of scaffolding proteins in experimental Parkinson's Disease (PD) as well as in L-DOPA induced dyskinesia. In particular, we have demonstrated the pivotal role of PSD-MAGUK proteins interaction with NMDA receptor subunits NR2A and NR2B in orchestrating the postsynaptic structural and functional apparatus of the glutamatergic synapse in experimental PD and in L-DOPA induced dyskinesia. Furthermore, preliminary findings of our group demonstrated that an aberrant increase of NR2A subunit at synaptic site is a key element of the glutamatergic synapse in an early model of experimental parkinsonism and is sensible to distinct degrees of dopamine denervation. Similarly, L-DOPA treated dyskinetic animals shows a highly significant increase of NR2A/NR2B subunits ratio at synaptic sites. Thus, it is of major relevance to understand the possibility of rescuing a correct NMDA receptor composition and motor activity in the early PD animal model and in dyskinetic animals by directly dissociating the PSD-MAGUKs/NR2A subunit interaction. To address this issue, we will investigate whether application of a cell-permeable TAT peptide fused to the last C-terminal nine aminoacids of NR2A (TAT- 2A) could reverse motor abnormalities in early parkinsonism and in L-DOPA induced dyskinesia via a normalization of NMDA receptor composition at synaptic sites, directly targeting the PSD-MAGUKs/NR2A subunit interaction and consequently, reducing NR2A abundance at synapses at control levels.