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

ABSTRACT: 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.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.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.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.

SUBMITTER: Feyder M

PROVIDER: S-EPMC4309747 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Feyder Michael M Södersten Erik E Santini Emanuela E Vialou Vincent V LaPlant Quincey Q Watts Emily L EL Spigolon Giada G Hansen Klaus K Caboche Jocelyne J Nestler Eric J EJ Fisone Gilberto G

Biological psychiatry 20140728 5

<h4>Background</h4>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.<h4>Methods</h4>6-Hydrox ...[more]

PMID: 25193242

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Project description:Vascular oxidative stress and inflammation play an important role in angiotensin II-induced hypertension, and mitogen-activated protein kinases participate in these processes. We questioned whether mitogen-activated protein kinase-activated protein kinase 2 (MK2), a downstream target of p38 mitogen-activated protein kinase, is involved in angiotensin II-induced vascular responses. In vivo experiments were performed in wild-type and Mk2 knockout mice infused intravenously with angiotensin II. Angiotensin II induced a 30 mm Hg increase in mean blood pressure in wild-type that was delayed in Mk2 knockout mice. Angiotensin II increased superoxide production and vascular cell adhesion molecule-1 in blood vessels of wild-type but not in Mk2 knockout mice. Mk2 knockdown by small interfering RNA in mouse mesenteric vascular smooth muscle cells caused a 42% reduction in MK2 protein and blunted the angiotensin II-induced 40% increase of MK2 expression. Mk2 knockdown blunted angiotensin II-induced doubling of intracellular adhesion molecule-1 expression, 2.4-fold increase of nuclear p65, and 1.4-fold increase in Ets-1. Mk2 knockdown abrogated the angiotensin II-induced 4.7-fold and 1.3-fold increase of monocyte chemoattractant protein-1 mRNA and protein. Angiotensin II enhanced reactive oxygen species levels (by 29%) and nicotinamide adenine dinucleotide phosphate oxidase activity (by 48%), both abolished by Mk2 knockdown. Reduction of MK2 blocked angiotensin II-induced p47phox translocation to the membrane, associated with a 53% enhanced catalase expression. Angiotensin II-induced increase of MK2 was prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor Nox2ds-tat. Mk2 small interfering RNA prevented the angiotensin II-induced 30% increase of proliferation. In conclusion, MK2 plays a critical role in angiotensin II signaling, leading to hypertension, oxidative stress via activation of p47phox and inhibition of antioxidants, and vascular inflammation and proliferation.

Dataset Information

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

Publications

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

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