Final Report Summary - PRIMLID (Priming for L-dopa-induced dyskinesia and neurotransmitter receptor trafficking dysregulation in parkinsonism)
Our observations suggest that overexpression of GRK6 significantly reduced the rotation frequency after repeated dopamine agonist treatment as compared to the control group. This effect could alleviates levodopa-induced dyskinesia in experimental Parkinson's Disease.
Our results suggest that ERK hyperactivation in several models of PD its correlates positively with LID severity. In fact, inhibition of this pathway with different doses of SL327, a specific chemical inhibitor of the ERK upstream kinase MEK1/2 attenuates LID.
L-dopa-induced dyskinesia associated with chronic L-dopa treatment in experimental rodents (using in vitro and in vivo modelling of PD and LID) and monkey parkinsonism is associated with a striatum-specific decrease in proteasome catalytic activity (Berthet et al., 2011, in revision).
Our data reveals profound reorganisation of the different proteasome subunits in response to dopaminergic challenges in a consistent manner across models (manuscript in preparation). In conclusion, this effort has allowed the fellow to participate in the making of several items, some of which are currently under revision.
We expect from these investigations to better understand the role of neurotransmitter receptor homologous desensitisation and its consequences upon signalling cascades, the canonical pathway and the mitogen-activated protein kinase cascade (MAPK) through activation of different scaffolds and also its implication in proteasome activity in the striatum, and bring grounds for better understanding of striatal dysfunctions in PD for therapeutic improvements with proof of concept studies in various experimental models of PD and LID.