A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and Delta FosB Expression - Université Pierre et Marie Curie Accéder directement au contenu
Article Dans Une Revue Biological Psychiatry Année : 2016

A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and Delta FosB Expression

Michael Feyder
  • Fonction : Auteur
Erik Sodersten
  • Fonction : Auteur
Emanuela Santini
  • Fonction : Auteur
Vincent Vialou
  • Fonction : Auteur
Quincey Laplant
  • Fonction : Auteur
Emily L. Watts
  • Fonction : Auteur
Giada Spigolon
  • Fonction : Auteur
Klaus Hansen
  • Fonction : Auteur
Eric J. Nestler
  • Fonction : Auteur
Gilberto Fisone
  • Fonction : Auteur

Résumé

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 Delta FosB- or Delta 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 Delta FosB produced by chronic L-DOPA was reduced in MSK1 knockout. Moreover, inducible overexpression of Delta FosB in striatonigral medium spiny neurons exacerbated dyskinetic behavior, whereas overexpression of Delta cJun, which reduces Delta 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 Delta FosB, which may occur via increased histone H3 phosphorylation at the fosB promoter. Results also show that accumulation of Delta FosB in striatonigral neurons is causally related to the development of dyskinesia.

Dates et versions

hal-01541323 , version 1 (19-06-2017)

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Michael Feyder, Erik Sodersten, Emanuela Santini, Vincent Vialou, Quincey Laplant, et al.. A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and Delta FosB Expression. Biological Psychiatry, 2016, 79 (5), pp.362-371. ⟨10.1016/j.biopsych.2014.07.019⟩. ⟨hal-01541323⟩
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