Parkinson disease is caused by the death of neurons that make dopamine, a chemical necessary for normal movement. This lack of dopamine is commonly treated by drug treatment with a precursor for dopamine, L-DOPA. L-DOPA is one of the only effective drug treatments for Parkinson disease. While L-DOPA treatment is very helpful for improving motor symptoms in the short term, long-term L-DOPA treatment leads to the development of abnormal uncontrollable movements and postures, called L-DOPA-induced dyskinesia and dystonia. Interestingly, the problem often continues even if L-DOPA treatment is stopped for brief stints, a so-called "drug holiday." This suggests that the way the brain reacts to L-DOPA treatment is "encoded" in a type of cellular memory program that is unleashed upon each L-DOPA dosage. From research in drug addiction and learning, we know that this long-term encoding is accomplished through lasting changes in the "openness" of DNA itself, allowing for particular genes to go through the process of transcription, the first step toward the production of new proteins. These new proteins are important for changing the structure of the brain to make abnormal movement possible after L-DOPA treatment. This environment-induced "openness" in the availability of genes is called epigenetics. The specific genes that are affected, the specific areas of DNA that are opened by epigenetics, and the specific types of cells involved in the response to L-DOPA treatment remain a mystery. As such, the overall goal of the current project is to understand changes in gene expression and associated changes in DNA availability to transcription that underlie the development of L-DOPA-induced dyskinesia and dystonia at the level of single cells within the primary motor area of the brain, the striatum.

In addition, the project aims to understand how these changes evolve as L-DOPA-induced dyskinesia and dystonia develops after L-DOPA treatment, establishing an "engram," or encoded memory pattern within cells, of the development of this side-effect in a model of Parkinson disease. In addition, I will attempt to interfere with the encoding of epigenetic changes after L-DOPA treatment by reducing a specific factor called deltaFosB that aids in "loosening up" DNA, making it easier for genes to be made into proteins through transcription. I hope that reducing deltaFosB will "tighten up" DNA, reducing the creation of certain proteins that contribute to abnormal movements upon LDOPA treatment. Since L-DOPA remains the main treatment for Parkinson disease and L-DOPA-induced dyskinesia and dystonia significantly impacts the quality of life of patients, this project has the potential to meet an unmet need for people with Parkinson disease. Indeed, more than half of people with Parkinson disease will experience motor-related side-effects within 5 years of beginning treatment with L-DOPA. Treatment and prevention of this side-effect will require knowledge of appropriate targets for halting the changes in the brain, at the cellular level. The output of this project is potentially groundbreaking for the Parkinson disease field, since it will provide data showing the particular changes in the expression of genes within a large number of individual cells, utilizing the most up-to-date technologies that science can currently provide. The changes revealed could then be targeted for development of new therapies immediately, and treatment options have the potential to be available within a few years.