Striatal histone modifications in models of levodopa-induced dyskinesia.

Anthony P. Nicholas, Farah D. Lubin, Penelope J. Hallett, Padmapriya Vattem, Paula Ravenscroft, Erwan Bezard, Shaobo Zhou, Susan H. Fox, Jonathan M. Brotchie, J. David Sweatt, David G. Standaert
J Neurochem. 2008-07-01; 106(1): 486-494
DOI: 10.1111/j.1471-4159.2008.05417.x

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1. J Neurochem. 2008 Jul;106(1):486-94. doi: 10.1111/j.1471-4159.2008.05417.x. Epub
2008 Jul 1.

Striatal histone modifications in models of levodopa-induced dyskinesia.

Nicholas AP(1), Lubin FD, Hallett PJ, Vattem P, Ravenscroft P, Bezard E, Zhou S,
Fox SH, Brotchie JM, Sweatt JD, Standaert DG.

Author information:
(1)Center for Neurodegeneration and Experimental Therapeutics, Department of
Neurology, University of Alabama at Birmingham, AL 35294-0017, USA.

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.

DOI: 10.1111/j.1471-4159.2008.05417.x
PMID: 18410512 [Indexed for MEDLINE]

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