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dc.contributor.authorNicholas, Anthony P.en_GB
dc.contributor.authorLubin, Farah D.en_GB
dc.contributor.authorHallett, Penelope J.en_GB
dc.contributor.authorVattem, Padmapriyaen_GB
dc.contributor.authorRavenscroft, Paulaen_GB
dc.contributor.authorBezard, Erwanen_GB
dc.contributor.authorZhou, Shaoboen_GB
dc.contributor.authorFox, Susan H.en_GB
dc.contributor.authorBrotchie, Jonathan M.en_GB
dc.contributor.authorSweatt, J. Daviden_GB
dc.contributor.authorStandaert, David G.en_GB
dc.date.accessioned2012-06-13T11:29:08Z
dc.date.available2012-06-13T11:29:08Z
dc.date.issued2008-07
dc.identifier.citationStriatal histone modifications in models of levodopa-induced dyskinesia. 2008, 106 (1):486-494 J. Neurochem.en_GB
dc.identifier.issn1471-4159
dc.identifier.pmid18410512
dc.identifier.doi10.1111/j.1471-4159.2008.05417.x
dc.identifier.urihttp://hdl.handle.net/10547/228773
dc.description.abstractDespite recent advances in the treatment of Parkinson disease (PD), levodopa remains the most effective and widely used therapy. A major limitation to the use of levodopa is the development of abnormal involuntary movements, termed levodopa-induced dyskinesia (LDID), following chronic levodopa treatment. Since recent studies have suggested that modifications of chromatin structure may be responsible for many long-lasting changes in brain function, we have examined post-translational modifications of striatal histones in two models of LDID: an acute murine model and a chronic macaque monkey model, both exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the primate model, which closely resembles human LDID, we observed that chronic levodopa and the appearance of LDID was associated with marked deacetylation of histone H4, hyperacetylation and dephosphorylation of histone H3, and enhancement of the phosphorylation of extracellular signal-regulated kinase (ERK). In the murine model of acutely rather than chronically induced LDID, dopamine depletion and levodopa treatment also induced deacetylation of histone H4 and phosphorylation of ERK, but histone H3 exhibited decreased trimethylation and reduced rather than enhanced acetylation. These data demonstrate striking changes in striatal histones associated with the induction of LDID in both animal models. The pattern of changes observed, as well as the behavioral features, differed in the two models. However, both models exhibit marked deacetylation of histone H4, suggesting that inhibitors of H4 deacetylation may be useful in preventing or reversing LDID.
dc.language.isoenen
dc.publisherWiley-Blackwellen_GB
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/18410512en_GB
dc.subject.mesh1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
dc.subject.meshAcetylation
dc.subject.meshAnimals
dc.subject.meshChromatin
dc.subject.meshChromosome Aberrations
dc.subject.meshCorpus Striatum
dc.subject.meshDisease Models, Animal
dc.subject.meshDopamine Agents
dc.subject.meshDyskinesia, Drug-Induced
dc.subject.meshExtracellular Signal-Regulated MAP Kinases
dc.subject.meshFemale
dc.subject.meshHistones
dc.subject.meshLevodopa
dc.subject.meshMacaca mulatta
dc.subject.meshMale
dc.subject.meshMethylation
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshParkinsonian Disorders
dc.subject.meshPhosphorylation
dc.subject.meshProtein Processing, Post-Translational
dc.subject.meshSpecies Specificity
dc.titleStriatal histone modifications in models of levodopa-induced dyskinesia.en
dc.typeArticleen
dc.contributor.departmentUniversity of Alabama at Birminghamen_GB
dc.identifier.journalJournal of neurochemistryen_GB
html.description.abstractDespite recent advances in the treatment of Parkinson disease (PD), levodopa remains the most effective and widely used therapy. A major limitation to the use of levodopa is the development of abnormal involuntary movements, termed levodopa-induced dyskinesia (LDID), following chronic levodopa treatment. Since recent studies have suggested that modifications of chromatin structure may be responsible for many long-lasting changes in brain function, we have examined post-translational modifications of striatal histones in two models of LDID: an acute murine model and a chronic macaque monkey model, both exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the primate model, which closely resembles human LDID, we observed that chronic levodopa and the appearance of LDID was associated with marked deacetylation of histone H4, hyperacetylation and dephosphorylation of histone H3, and enhancement of the phosphorylation of extracellular signal-regulated kinase (ERK). In the murine model of acutely rather than chronically induced LDID, dopamine depletion and levodopa treatment also induced deacetylation of histone H4 and phosphorylation of ERK, but histone H3 exhibited decreased trimethylation and reduced rather than enhanced acetylation. These data demonstrate striking changes in striatal histones associated with the induction of LDID in both animal models. The pattern of changes observed, as well as the behavioral features, differed in the two models. However, both models exhibit marked deacetylation of histone H4, suggesting that inhibitors of H4 deacetylation may be useful in preventing or reversing LDID.


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