Matthieu Bastide, Erwan Bézard et al. in Neurobiol Dis.

Involvement of transcriptional mechanisms in L-DOPA induced dyskinesia

Striatal NELF-mediated RNA polymerase II stalling controls l-dopa induced dyskinesia. Bastide MF, Bido S, Duteil N, Bézard E.
Neurobiol Dis. 2015 Oct 19;85:93-98. doi: 10.1016/j.nbd.2015.10.013.

Involvement of transcriptional mechanisms in L-DOPA induced dyskinesia

Chronic treatment of Parkinson’s disease (PD) patients with the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) induces the development of involuntary movements, known as L-DOPA-induced dyskinesia (LID). LID result in a rapid striatal overexpression of several molecular markers, in particular the members of the immediate-early gene (IEG) family, a class of genes rapidly transcribed in response to an external stimulus, including ΔFosB, ARC and Zif268. Down-regulating the expression of ∆FosB or inactivating ∆FosB-expressing neurons, decrease LID severity both in rodents and non-human primates. These data highlight the key role of IEG in LID manifestation. However, the transcriptional-related mechanisms inducing a rapid IEG expression in LID remain unclear. Recent evidences suggest that expression of many IEG depends on a prior recruitment of the RNA polymerase II, which initiates transcription elongation and stalls after transcribing a short piece of mRNA near the promoter. RNA polymerase II stalling is critically regulated by a protein complex, the negative elongation factor (NELF), composed of four essential subunits: NELF-A, -B, -C/D and –E. NELF-mediated RNA polymerase II stalling on IEG promoters poises them for rapid transcription within few minutes after an external stimulus . While the in vitro machinery is well described, the role of NELF-mediated RNA polymerase II stalling remains however to be demonstrated in vivo in physiological and pathological states.

Therefore, to assess the precise role of NELF-mediated RNA polymerase II stalling upon LID severity, we decrease the levels of the NELF essential subunit NELF-E using a lentiviral vector (LV) delivering a short spin RNA (shRNA) against NELF-E mRNA in the striatum of dyskinetic 6-hydroxydopamine (6-OHDA) lesioned rats. The depletion of NELF-E reduced the severity of LID manifestation without affecting the beneficial effect of L-Dopa associated with a decrease in ΔFosB, ARC and Zif268 expression.

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