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

Abstract

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
• Transcription
• Stalling
• Parkinson's disease
• Rat model