Dysregulation of BET proteins in levodopa-induced dyskinesia.

Academic Article

Abstract

  • Levodopa (L-DOPA) remains the most effective pharmacological treatment for Parkinson Disease (PD) but its use is limited by the development of debilitating drug-related side effects, particularly L-DOPA induced dyskinesia (LID). LID is a consequence of long-term L-DOPA use, and in model systems is characterized by a "priming effect", whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent dopaminergic stimulation. Preliminary studies into the mechanisms underlying this cellular memory have indicated an important role for epigenetic change but many of the downstream mechanisms remain unknown. The family of bromodomain and extraterminal (BET) proteins, which bind acetylated histones, play a critical effector role in the regulation of transcription. BET proteins have been implicated in several forms of neural plasticity, but their potential relevance to LID remains unexplored. Using the 6-OHDA rodent model of LID, we show that dyskinesia development induces alterations in BET protein expression along with enhanced occupation of sites at the promoter and enhancer regions of genes dysregulated during dyskinesia development. When BET function was blocked using the pharmacologic inhibitor JQ1, LID was prevented. In addition, we found that JQ1 treatment blocked the transcriptional upregulation of several immediate-early genes known to participate in the pathogenesis of dyskinesia. Together, these results demonstrate an essential role for BET protein activity as an epigenetic "reader" of the altered histone acetylation required for LID development and suggest that modulation of BET protein function is a potential therapeutic avenue for the prevention or reversal of LID in PD.
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    Keywords

  • BET proteins, Dyskinesia, JQ1, L-DOPA, Animals, Antiparkinson Agents, Azepines, Chromatin Immunoprecipitation, Corpus Striatum, Disease Models, Animal, Dyskinesia, Drug-Induced, Levodopa, Male, Oxidopamine, Parkinsonian Disorders, Protein Domains, Proteins, RNA, Messenger, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Transcription, Genetic, Triazoles
  • Digital Object Identifier (doi)

    Author List

  • A Figge D; Standaert DG
  • Start Page

  • 125
  • End Page

  • 132
  • Volume

  • 102