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

详细信息    查看全文

• 作者：Michael Feyder^a ; Erik Sö ; dersten^a ; ^b ; Emanuela Santini^a ; Vincent Vialou^c ; ^d ; Quincey LaPlant^c ; Emily L. Watts^c ; Giada Spigolon^a ; Klaus Hansen^b ; Jocelyne Caboche^d ; Eric J. Nestler^c ; Gilberto Fisone^a ; ^{gilberto.fisone@ki.se" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Dopamine D1 receptor ; Histone ; Medium spiny neurons ; Mouse ; Parkinson&rsquo ; s disease ; Striatum
• 刊名：Biological Psychiatry
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：79
• 期：5
• 页码：362-371
• 全文大小：3408 K

文摘

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.