All ETDs from UAB

Advisory Committee Chair

David G Standaert

Advisory Committee Members

David Sweatt

Erik Roberson

Lucas Pozzo-Miller

Haydeh Payami

Robin G Lorenz

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Levodopa-induced dyskinesia (LID) is a persistent behavioral sensitization that develops after repeated levodopa (L-DOPA) exposure in Parkinson disease (PD) patients. LID is characterized by a “priming effect”, whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent administrations of L-DOPA. In neurons, transcriptional regulation through dynamic changes to epigenetic modifications, including DNA methylation and histone acetylation, have been shown pivotal to many long-term behavioral modifications; however, their role in LID has been minimally explored. Using a rodent model, we show LID development leads to the aberrant expression of DNA demethylating enzymes and locus-specific changes to DNA methylation at the promoter regions of genes aberrantly transcribed following L-DOPA treatment. Looking for dynamic DNA methylation in LID genome-wide, we used reduced representation bisulfite sequencing and found an extensive reorganization of the dorsal striatal methylome. LID development led to significant demethylation at many important regulatory areas of aberrantly transcribed genes. We then used pharmacologic treatments that alter DNA methylation bi-directionally and found them sufficient to modulate dyskinetic behaviors. Although this early evidence indicates that alterations in epigenetic modifications are involved in the development of LID, the proteins necessary for the functional interpretation of these marks remains a mystery. To address this issue, we further show that dyskinesia development induces alterations in bromodomain and extraterminal motif (BET) protein expression, known readers of histone acetylation, leading to their enhanced occupation at the promoter and enhancer regions of genes aberrantly transcribed following dyskinesia development. When BET function is blocked using a pharmacologic inhibitor, JQ1, it was found sufficient to hinder LID development. We further assessed JQ1's effect on the striatal sensitization necessary to LID expression finding it capable of blocking the sensitized transcription of several immediate early genes by inhibiting the identified enhancements in BET protein binding. Together, these findings demonstrate that L-DOPA induces widespread changes to the striatal epigenome, and that aberrant regulation of these modifications is required for the transcriptional dysfunction and maintenance of LID.

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