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.
Keywords
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Article info
Publication history
Published online: July 28, 2014
Accepted:
July 15,
2014
Received in revised form:
June 29,
2014
Received:
March 25,
2014
Identification
Copyright
© 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Unraveling the Mechanism of Dyskinesia One Transcription Factor at a TimeBiological PsychiatryVol. 79Issue 5
- PreviewL-DOPA–induced dyskinesia (LID), or abnormal involuntary movements, is a common side effect of L-DOPA therapy in patients with Parkinson’s disease. When L-DOPA is initially administered, it effectively reverses akinesia caused by the loss of dopamine. However, long-term L-DOPA administration produces a hyperkinetic effect, triggering excessive movements in human patients and in animal models. The mechanisms of LID have been under intense investigation for decades, and numerous important discoveries in the past several years established the key mechanisms of LID development.
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