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Striatal histone modifications in models of levodopa-induced dyskinesia.

  • Shaobo Zhou
    ,
  • Anthony P. Nicholas
    ,
  • Farah D. Lubin
    ,
  • Penelope J. Hallett
    ,
  • Padmapriya Vattem
    ,
  • Paula Ravenscroft
  • Department of Veterans Affairs
    ,
  • University of Alabama at Birmingham
    ,
  • Massachusetts General Hospital
    ,
  • University of Manchester
    ,
  • Université Victor Segalen Bordeaux 2
    ,
  • Toronto Western Hospital
Research Output: Contribution to journal Article Peer-review

Sustainable Development Goals

  • SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well

Abstract

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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 486-494

Journal (Volume, Issue Number)

Journal of Neurochemistry (Volume 106, Issue 1)

Publication milestones

  • Published - 01/07/2008

Publication status

Published - 01/07/2008

ISSN

0022-3042

External Publication IDs

  • handle.net: 10547/228773
  • Scopus: 45249099791

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