Manipulating Gene Expression in the Dyskinesias of Parkinson's Disease

DESCRIPTION (provided by applicant): This project addresses one of the most disabling complications of dopaminergic therapy in Parkinson's disease, namely the development of involuntary movements named dyskinesias. The mechanisms underlying dyskinesias remain unknown, and we lack specific and effective treatments to eradicate them. Studies in animal models have shown that the striatal levels of the chronic transcription factor ?FosB consistently increase during chronic levodopa treatment. Therefore, it has been hypothesized that ?FosB may regulate the genes responsible for altered responses to dopaminergic drugs. Here, we will test the effects of the transgenic manipulation of ?FosB protein expression in non-human primates. The novel approach taken in this project may address pathophysiologic aspects and help develop new therapies. The project includes three specific aims. In the first aim, we will assess the behavioral and molecular changes following the overexpression of ?FosB in the striatum of parkinsonian monkeys using a viral vector-mediated gene delivery. The second aim will examine the basal ganglia circuitry of these animals using electrophysiologic recordings and correlate them with the development of dyskinesias. And the third aim will confirm the role of ?FosB by down-regulating the expression of the endogenous gene in rats and monkeys. This project employs diverse experimental approaches across disciplines to address an important health problem. From the construction of viral vectors, to the in vitro testing, to the final evaluations of motor behavior and physiologic correlates in primates, this sequence of translational studies is designed to establish the mechanistic role of ?FosB in the development of dyskinesias. Furthermore, these studies will assess the clinical application of ?FosB gene silencing as a therapeutic strategy in complicated Parkinson's disease.