Striatal histone modifications in models of levodopa-induced dyskinesia

• Published in: Journal of neurochemistry Vol. 106; no. 1; pp. 486 - 494
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.07.2008; Blackwell Publishing Ltd; Blackwell
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; acetylation; Acetylation - drug effects; Animals; Biochemistry; Biological and medical sciences; Brain; Chromatin - drug effects; Chromatin - genetics; Chromatin - metabolism; Chromosome Aberrations - drug effects; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - physiopathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine Agents - toxicity; dyskinesia; Dyskinesia, Drug-Induced - genetics; Dyskinesia, Drug-Induced - metabolism; Dyskinesia, Drug-Induced - physiopathology; epigenetics; Extracellular Signal-Regulated MAP Kinases - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; histone deacetylase inhibitors; Histones - drug effects; Histones - genetics; Histones - metabolism; Levodopa - toxicity; Macaca; Macaca mulatta; macaque; Male; Medical sciences; Methylation - drug effects; Mice; Mice, Inbred C57BL; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Parkinson disease; Parkinson's disease; Parkinsonian Disorders - drug therapy; Pharmacology; Phosphorylation - drug effects; Primates; Protein Processing, Post-Translational - drug effects; Protein Processing, Post-Translational - genetics; Species Specificity; Modification; Animal model; Parkinson's disease; Central nervous system; Monkey; Parkinson disease; Abnormal movement; epigenetics; Encephalon; Involuntary movement; acetylation; Primates; Development; Degenerative disease; Levodopa; Neurological disorder; Histone; Dyskinesia; histone deacetylase inhibitors; macaque; Nervous system diseases; Acute; Rodentia; Basal ganglion; Corpus striatum; Catecholamine; Cerebral disorder; Vertebrata; Chronic; Mammalia; Treatment; Mouse; Central nervous system disease; Neurotransmitter; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05417.x

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.