Striatal histone modifications in models of levodopa-induced dyskinesia

Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, AL 35294-0017, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 08/2008; 106(1):486-94. DOI: 10.1111/j.1471-4159.2008.05417.x
Source: PubMed


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.

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Available from: Erwan Bezard, Sep 03, 2014
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    • "yl - 1 , 2 , 3 , 6 - tetrahydropyridin ( MPTP ) that induces dopamine depletion have been associated with reduced striatal H3K4me3 ( Nicholas et al . , 2008 ) . Conversely , raising dopamine level by administration of the dopamine precursor levodopa partially ameliorates the symptoms and correlates with deacetylation of H4K5 , K8 , K12 , and K16 ( Nicholas et al . , 2008 ) ."
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