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Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?
Pharmacol Ther. 2013 Oct; 140(1):34-52.P&T

Abstract

Parkinson's disease (PD) is the most common movement disorder affecting more than 4million 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?

Authors+Show Affiliations

Parkinson's Disease Research Group, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK. Electronic address: ian.harrison09@imperial.ac.uk.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

23711791

Citation

Harrison, Ian F., and David T. Dexter. "Epigenetic Targeting of Histone Deacetylase: Therapeutic Potential in Parkinson's Disease?" Pharmacology & Therapeutics, vol. 140, no. 1, 2013, pp. 34-52.
Harrison IF, Dexter DT. Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease? Pharmacol Ther. 2013;140(1):34-52.
Harrison, I. F., & Dexter, D. T. (2013). Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease? Pharmacology & Therapeutics, 140(1), 34-52. https://doi.org/10.1016/j.pharmthera.2013.05.010
Harrison IF, Dexter DT. Epigenetic Targeting of Histone Deacetylase: Therapeutic Potential in Parkinson's Disease. Pharmacol Ther. 2013;140(1):34-52. PubMed PMID: 23711791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease? AU - Harrison,Ian F, AU - Dexter,David T, Y1 - 2013/05/24/ PY - 2013/03/01/received PY - 2013/05/09/accepted PY - 2013/5/29/entrez PY - 2013/5/29/pubmed PY - 2014/4/8/medline KW - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine KW - 1-methyl-4-phenylpyridinium KW - 3,4-Dihydroxyphenylacetic acid KW - 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide KW - 6-OHDA KW - 6-hydroxydopamine KW - AD KW - ALS KW - Ac KW - Ac-Lys KW - Alzheimer's disease KW - Amylotrophic Lateral Sclerosis KW - BBB KW - BDNF KW - CBP KW - DA KW - DNA KW - DNA methyltranferases KW - DNMT KW - DOPAC KW - Epigenetics KW - FDA KW - Food and Drug Administration KW - GABA KW - GDNF KW - GNAT KW - GSK-3 KW - Gcn5-related acetyltransferases KW - HAT KW - HD KW - HDAC KW - HDACI KW - HDM KW - HMT KW - HPLC KW - HSP KW - HVA KW - Histone deacetylase KW - Histone deacetylase inhibitor KW - Huntington's disease KW - LPS KW - LSD KW - Lys KW - MAO KW - MOZ Ybf2/Sas3 Sas2 and Tip60 KW - MPP+ KW - MPTP KW - MTT KW - MYST KW - Me KW - MeCP2 KW - NAD+ KW - Neurodegeneration KW - Neuroprotection KW - PD KW - PE KW - Parkinson's disease KW - S-adenosyl-homocysteine KW - S-adenosyl-methionine KW - SAH KW - SAHA KW - SAM KW - SCFA KW - SIR2 KW - SNpc KW - SOD KW - Substantia Nigra pars compacta KW - TH KW - TSA KW - acetyl KW - acetyl-lysine KW - blood brain barrier KW - brain derived neurotrophic factor KW - deoxyribonucleic acid KW - dopamine KW - glial derived neurotrophic factor KW - glycogen synthase kinase 3 KW - heat shock protein KW - high performance liquid chromatography KW - histone acetyltransferases KW - histone deacetylase KW - histone deacetylase inhibitor KW - histone demethylases KW - histone methyl-transferases KW - homovanillic acid KW - lipopolysaccharide KW - lysine KW - lysine-specific histone demethylase KW - methyl KW - methyl-CpG binding protein 2 KW - monoamine oxidase KW - nicotinamide adenine dinucleotide KW - p300/CREB binding protein KW - phycoerythrin KW - qRT-PCR KW - quantitative real time polymerase chain reaction KW - short chain fatty acid KW - silent information regulator 2 KW - suberoylanilide hydroxamic acid KW - superoxide dismutase KW - trichostatin A KW - tyrosine hydroxylase KW - α-synuclein KW - αSyn KW - γ-Aminobutyric acid SP - 34 EP - 52 JF - Pharmacology & therapeutics JO - Pharmacol Ther VL - 140 IS - 1 N2 - Parkinson's disease (PD) is the most common movement disorder affecting more than 4million 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? SN - 1879-016X UR - https://www.unboundmedicine.com/medline/citation/23711791/Epigenetic_targeting_of_histone_deacetylase:_therapeutic_potential_in_Parkinson's_disease L2 - https://linkinghub.elsevier.com/retrieve/pii/S0163-7258(13)00125-3 DB - PRIME DP - Unbound Medicine ER -