title: A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and ∆FosB Expression.
abstract: BACKGROUND
  Abnormal regulation of extracellular signal-regulated kinases 1 and 2 has been implicated in 3,4-dihydroxy-l-phenylalanine (L-DOPA)-induced dyskinesia (LID), a motor complication affecting Parkinson's disease patients subjected to standard pharmacotherapy. We examined the involvement of mitogen- and stress-activated kinase 1 (MSK1), a downstream target of extracellular signal-regulated kinases 1 and 2, and an important regulator of transcription in LID.
  
  
  METHODS
  6-Hydroxydopamine was used to produce a model of Parkinson's disease in MSK1 knockout mice and in ∆FosB- or ∆cJun-overexpressing transgenic mice, which were assessed for LID following long-term L-DOPA administration. Biochemical processes were evaluated by Western blotting or immunofluorescence. Histone H3 phosphorylation was analyzed by chromatin immunoprecipitation followed by promotor-specific quantitative polymerase chain reaction.
  
  
  RESULTS
  Genetic inactivation of MSK1 attenuated LID and reduced the phosphorylation of histone H3 at Ser10 in the striatum. Chromatin immunoprecipitation analysis showed that this reduction occurred at the level of the fosB gene promoter. In line with this observation, the accumulation of ∆FosB produced by chronic L-DOPA was reduced in MSK1 knockout. Moreover, inducible overexpression of ∆FosB in striatonigral medium spiny neurons exacerbated dyskinetic behavior, whereas overexpression of ∆cJun, which reduces ∆FosB-dependent transcriptional activation, counteracted LID.
  
  
  CONCLUSIONS
  Results indicate that abnormal regulation of MSK1 contributes to the development of LID and to the concomitant increase in striatal ∆FosB, which may occur via increased histone H3 phosphorylation at the fosB promoter. Results also show that accumulation of ∆FosB in striatonigral neurons is causally related to the development of dyskinesia.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Feyder
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Erik
authors.initials: E
authors.lastname: Södersten
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Institut National de la Santé et de la Recherche Médicale, Le Centre national de la recherche scientifique Unités Mixtes de Recherche 7224, Université Pierre et Marie Curie, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vialou
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Quincey
authors.initials: Q
authors.lastname: LaPlant
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Watts
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Giada
authors.initials: G
authors.lastname: Spigolon
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Le Centre national de la recherche scientifique Unités Mixtes de Recherche 7224, Université Pierre et Marie Curie, Paris, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caboche
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: gilberto.fisone@ki.se.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017072:Neostriatum / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D016627:Oxidopamine / Q000008:administration & dosage; D010300:Parkinson Disease / Q000150:complications*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; D007980:Levodopa; D016627:Oxidopamine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Dopamine D(1) receptor; Histone; Medium spiny neurons; Mouse; Parkinson’s disease; Striatum