Striatal NELF-mediated RNA polymerase II stalling controls L-dopa induced dyskinesia

Neurobiol Dis. 2016 Jan:85:93-98. doi: 10.1016/j.nbd.2015.10.013. Epub 2015 Oct 19.


Long-term l-3,4-dihydroxyphenylalanine (L-Dopa) treatment in Parkinson's disease leads to involuntary movements called dyskinesia, notably through an overexpression of immediate-early genes (IEG). Their rapid transcription involves the stalling of RNA polymerase II on IEG promoters, a mechanism that critically depends on the presence of the negative elongation factor (NELF) protein complex. We here down-regulated the key NELF-E subunit using lentiviral vector delivery of a short hairpin RNA in the striatum of 6-hydroxydopamine lesioned rats. Such NELF-E reduced expression significantly attenuated the development of abnormal involuntary movements in response to chronic L-Dopa treatment. Effectiveness of silencing was demonstrated by the significant decrease in striatal ∆FosB, ARC and Zif268 IEG expression. Repression of NELF-mediating RNA polymerase II stalling thus achieves both antidyskinetic and potentiation of antiparkinsonian L-Dopa effect, highlighting the role of transcriptional events in dyskinesia establishment, acute dyskinetic manifestation and in the therapeutic response to L-Dopa.

Keywords: Immediate-early genes; Parkinson's disease; Rat model; Stalling; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / toxicity
  • Cell Culture Techniques
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced / metabolism*
  • Early Growth Response Protein 1 / metabolism
  • Levodopa / toxicity*
  • Male
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA Polymerase II / metabolism*
  • Rats, Sprague-Dawley
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Antiparkinson Agents
  • Cytoskeletal Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • Fosb protein, rat
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • Transcription Factors
  • activity regulated cytoskeletal-associated protein
  • negative elongation factor
  • Levodopa
  • RNA Polymerase II