The broad aim of this proposal is to test the hypothesis that L-dopa-induced dyskinesias (LID) in Parkinson's disease (PD) arise at least in part from non-uniform dopaminergic denervation of the striatum, whereby islands of dopaminergic activity (hotspots) are created within the most severely affected part of the striatum, the post-commissural putamen. Transduced with an AAV containing the cDNA for aromatic L- amino acid decarboxylase (AADC), striatal neurons gain the ability to produce dopamine (DA) from exogenous L-Dopa, a DA precursor. During testing in a non-human primate (NHP) model of PD, we observed severe LID when AAV-AADC was infused into the striatum in a way that generated focal regions of high AADC activity. More recently, we have found that the generation of a single AADC hotspot in the post-commissural putamen of a hemi-parkinsonian monkey generated LID, remarkable because this model is almost completely refractory to LID. We plan to use an inducible AADC expression vector, recently shown to be effective in a parkinsonian rodent model. With this tool, we should be able to produce hotspots in monkey brain reversibly. This in turn should allow us to ask whether turning AADC hotspots on and off correlates with induction and abatement of LID. We will also be able to ask what kinds of metabolic and molecular changes occur with onset of LID, and whether such changes are reversed upon elimination of the hotspot. This research program is important from three perspectives. First, it promises to establish an in vivo model of LID in which neural correlates of LID can be investigated in a controlled setting. Second, it seeks to test important hypotheses regarding the mechanistic and anatomical origins of L-Dopa-dependent dyskinesias. Finally, it investigates two likely causes of post-engraftment dyskinesias, which are perhaps the most important current impediment to progress in transplantation-based therapies for PD. This work will provide insight on the mechanisms behind L-dopa induced dyskinesias and will provide a basis for using gene therapy approaches to treat patients with Parkinson's disease. ? ? ?
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