Striatal NELF-mediated RNA polymerase II stalling controls L-dopa induced dyskinesia.
Neurobiology of Disease. 2016-01-01; 85: 93-98
DOI: 10.1016/j.nbd.2015.10.013
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1. Neurobiol Dis. 2016 Jan;85:93-98. doi: 10.1016/j.nbd.2015.10.013. Epub 2015 Oct
19.
Striatal NELF-mediated RNA polymerase II stalling controls L-dopa induced
dyskinesia.
Bastide MF(1), Bido S(1), Duteil N(1), Bézard E(2).
Author information:
(1)Univ. de Bordeaux, Institut des Maladies Neurodégénératives,UMR 5293,33000
Bordeaux,France; CNRS,Institut des Maladies Neurodégénératives,UMR 5293,33000
Bordeaux,France.
(2)Univ. de Bordeaux, Institut des Maladies Neurodégénératives,UMR 5293,33000
Bordeaux,France; CNRS,Institut des Maladies Neurodégénératives,UMR 5293,33000
Bordeaux,France. Electronic address: .
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.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2015.10.013
PMID: 26480869 [Indexed for MEDLINE]