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Striatal histone modifications in models of levodopa‐induced dyskinesia
Author(s) -
Nicholas Anthony P.,
Lubin Farah D.,
Hallett Penelope J.,
Vattem Padmapriya,
Ravenscroft Paula,
Bezard Erwan,
Zhou Shaobo,
Fox Susan H.,
Brotchie Jonathan M.,
Sweatt J. David,
Standaert David G.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05417.x
Subject(s) - acetylation , levodopa , histone , dyskinesia , histone h4 , phosphorylation , chromatin , biology , neuroscience , pharmacology , cancer research , microbiology and biotechnology , medicine , parkinson's disease , biochemistry , disease , dna , gene
Despite 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.