title: 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.
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France; CNRS,Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France.
authors.forename: Matthieu F
authors.initials: MF
authors.lastname: Bastide
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France; CNRS,Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France.
authors.forename: Simone
authors.initials: S
authors.lastname: Bido
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France; CNRS,Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Duteil
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France; CNRS,Institut des Maladies Neurodégénératives,UMR 5293,33000 Bordeaux,France. Electronic address: erwan.bezard@u-bordeaux.fr.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bézard
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D018929:Cell Culture Techniques; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D003598:Cytoskeletal Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C483820:Fosb protein, rat; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; C092069:activity regulated cytoskeletal-associated protein; C118437:negative elongation factor; D007980:Levodopa; D012319:RNA Polymerase II
keywords: Immediate-early genes; Parkinson's disease; Rat model; Stalling; Transcription