title: Gene expression analyses identify Narp contribution in the development of L-DOPA-induced dyskinesia.
abstract: In Parkinson's disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by L-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0-6 h after treatment with L-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by l-DOPA. l-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment with L-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after L-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalating L-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced by L-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes, Nptx2, in the development of LID.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm, UMR-S 1127, ICM, Pitié-Salpêtrière Hospital, 75013 Paris, France, CNRS, UMR 7225, 75013 Paris, France, Assistance Publique Hôpitaux de Paris, Department of Pharmacy, Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Charbonnier-Beaupel
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm, UMR-S 1127, ICM, Pitié-Salpêtrière Hospital, 75013 Paris, France, CNRS, UMR 7225, 75013 Paris, France, Inserm UMR-S 839, 75005 Paris, France, Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Malerbi
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm UMR-S 839, 75005 Paris, France, Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alcacer
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm, UMR-S 1127, ICM, Pitié-Salpêtrière Hospital, 75013 Paris, France, CNRS, UMR 7225, 75013 Paris, France.
authors.forename: Khadija
authors.identifier: http://orcid.org/0000-0002-1039-8126
authors.initials: K
authors.lastname: Tahiri
authors.affiliation: UPMC Univ Paris 06, Post genomic platform P3S, 75013 Paris, France.
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.affiliation: Departments of Molecular Virology, Immunology and Medical Genetics, Neuroscience and Neurological Surgery, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Chuansong
authors.identifier: http://orcid.org/0000-0003-4501-2518
authors.initials: C
authors.lastname: Wang
authors.affiliation: Departments of Molecular Virology, Immunology and Medical Genetics, Neuroscience and Neurological Surgery, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Matthew
authors.initials: M
authors.lastname: During
authors.affiliation: Johns Hopkins University School of Medicine, Solomon H. Snyder Department of Neuroscience, Baltimore, Maryland 21205, and.
authors.forename: Desheng
authors.initials: D
authors.lastname: Xu
authors.affiliation: Johns Hopkins University School of Medicine, Solomon H. Snyder Department of Neuroscience, Baltimore, Maryland 21205, and.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm UMR-S 839, 75005 Paris, France, Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm UMR-S 839, 75005 Paris, France, Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm, UMR-S 1127, ICM, Pitié-Salpêtrière Hospital, 75013 Paris, France, CNRS, UMR 7225, 75013 Paris, France, Assistance Publique Hôpitaux de Paris, Inserm, Clinical Investigation Center, CIC-1422, Pitié-Salpêtrière Hospital, 75013 Paris, France jean-christophe.corvol@psl.aphp.fr.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000235:genetics*; D004409:Dyskinesia, Drug-Induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D000099153:Pentraxins
chemical_list: D000978:Antiparkinson Agents; D002097:C-Reactive Protein; D007980:Levodopa; D009419:Nerve Tissue Proteins; D000099153:Pentraxins
keywords: Narp; Parkinson's disease; l-DOPA-induced dyskinesia; transcriptome