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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    • "Whatever the exact mechanism behind increased D1R signaling, stimulation of these receptors causes activation of the cyclic AMP (cAMP)/protein kinase A (PKA)/DARPP-32 (DA- and cAMP-regulated phosphoprotein, 32 kDa)/protein phosphatase 1 (PP-1) pathway and the mitogen activated protein kinase (MAPK) pathway, which culminates in phosphorylation of extracellular signal related kinase (ERK1/2) (94). This results in DNA modifications (95, 96) and increased expression of transcription factors, especially ΔFosB/FosB (97), which are indicative of long-term cellular adaptations. "
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    ABSTRACT: Dopamine replacement therapy in the form of levodopa results in a significant proportion of patients with Parkinson's disease developing debilitating dyskinesia. This significantly complicates further treatment and negatively impacts patient quality of life. A greater under-standing of the neurobiological mechanisms underlying levodopa-induced dyskinesia (LID) is therefore crucial to develop new treatments to prevent or mitigate LID. Such investiga-tions in humans are largely confined to assessment of neurochemical and cerebrovascular blood flow changes using positron emission tomography and functional magnetic reso-nance imaging. However, recent evidence suggests that LID is associated with specific morphological changes in the frontal cortex and midbrain, detectable by structural MRI and voxel-based morphometry. Current human neuroimaging methods however lack sufficient resolution to reveal the biological mechanism driving these morphological changes at the cellular level. In contrast, there is a wealth of literature from well-established rodent mod-els of LID documenting detailed post-mortem cellular and molecular measurements. The combination therefore of advanced neuroimaging methods and rodent LID models offers an exciting opportunity to bridge these currently disparate areas of research. To highlight this opportunity, in this mini-review, we provide an overview of the current clinical evidence for morphological changes in the brain associated with LID and identify potential cellular mechanisms as suggested from human and animal studies. We then suggest a framework for combining small animal MRI imaging with rodent models of LID, which may provide important mechanistic insights into the neurobiology of LID.
    Frontiers in Neurology 06/2014; 5. DOI:10.3389/fneur.2014.00095
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    • "This has great implications in PD in that the treatment of patients with MAO inhibitors such as Selegiline and Rasagaline could contribute to the rectification of the reduced H3-Lys4 levels previously described in PD models by Nicholas et al. (2008). Nevertheless, far greater understanding of the role of LSD1 in PD is required to understand how this could contribute to disease aetiology and pathophysiology. "
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    ABSTRACT: Parkinson's disease (PD) is the most common movement disorder affecting more than 4 million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD?
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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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    ABSTRACT: From fertilization throughout development and until death, cellular programs in individual cells are dynamically regulated to fulfill multiple functions ranging from cell lineage specification to adaptation to internal and external stimuli. Such regulation is of major importance in brain cells, because the brain continues to develop long after birth and incorporates information from the environment across life. When compromised, these regulatory mechanisms can have detrimental consequences on neurodevelopment and lead to severe brain pathologies and neurodegenerative diseases in the adult individual. Elucidating these processes is essential to better understand their implication in disease etiology. Because they are strongly influenced by environmental factors, they have been postulated to depend on epigenetic mechanisms. This review describes recent studies that have identified epigenetic dysfunctions in the pathophysiology of several neurodevelopmental and neurodegenerative diseases. It discusses currently known pathways and molecular targets implicated in pathologies including imprinting disorders, Rett syndrome, and Alzheimer, Parkinson and Hungtinton disease, and their relevance to these diseases.
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