PRIMLID

Priming for L-dopa-induced dyskinesia and neurotransmitter receptor trafficking dysregulation in parkinsonism

 Partecipanti

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 Obiettivo del progetto (Objective)

'L-dopa-induced dyskinesia (LID) severely limits the usability of L-dopa in Parkinson’s disease (PD) patients and a treatment is needed to improve their quality of life. The project aims at elucidating the “priming” phenomenon in PD, i.e. the unchangeable modification of brain response to dopamine (DA), that leads to the development of LID. We will investigate the role of neurotransmitter receptor homologous desensitization and its consequences upon main intracellular signalling cascades, i.e. the canonical pathway and the mitogen-activated protein kinase cascade (MAPK) through activation of different scaffolds, in various experimental models: namely an in vitro nigrostriatal slice model, the rat model of abnormal involuntary movements and the non-human primate model of LID. The program aims at elucidating the priming pathophysiology onto which we would then develop proof-of-concepts treatment approaches using TAT-peptides specific of the different docking domains of ERK1/2 for discriminating between the cytosolic and nuclear effects of this cascade. SA1: To be continued throughout the project for producing the in vitro parasagittal nigrostriatal slice culture model and the rat experimental model. Tissus from non-human primates are already available. SA 2: Real-time study of DA and mGlu receptor trafficking using quantum dot imaging on primary striatal cultures. SA3: Time course of subcellular trafficking of DA and mGluR receptors, of the protein machinery of homologous desensitization (GRK/arrestin) in DA-depleted cultures/brains that have never been in contact with a dopamimetic (immunohistochemistry – light, deconvolution of fluorescence, electron microscopy – subcellular fractionation). SA5: Behavioral impact of specific blockade of cytosolic vs. nuclear targets of ERK1/2 using TAT peptides functional antagonists of the ERK1/2 docking domains– role in priming and dyskinesia manifestations –behavior, stereotactic surgery – functional anatomy)'