Final Report Summary - PRIMLID (Priming for L-dopa-induced dyskinesia and neurotransmitter receptor trafficking dysregulation in parkinsonism) The fellow has worked in different training activities mainly focused to development of 'in vitro' and 'in vivo' rodent model of PD and LID (SA1). Previously, fellow has gained experience in the development of 6-OHDA models of PD and LID, included animal handling and behavioural assessment. Later, the fellow was focused on acquiring experience in many of the techniques necessary for the development of the project, involving morphological and imaging techniques as well as molecular biology. Besides, fellow has performed primary striatal cell culture and parasagittal nigrostriatal and/or striatal slice culture in rodent. Finally, fellow has performed some point such as SA2-SA5. In fact, fellow tested the arrestins/GRKS and ERK roles in LID. Additionally, fellow has collaborated in another research lines, with different members of this laboratory. These research lines are closely related with the role of neurotransmitter receptor homologous desensitisation and its consequences upon main intracellular signalling cascades, such as the proteasome role in the dysregulation of dopamine D1 receptor trafficking in parkinsonism and dyskinetic state. 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.
