title: Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?
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.affiliation: 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.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Harrison
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D057890:Epigenomics; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-methyl-4-phenylpyridinium; 3,4-Dihydroxyphenylacetic acid; 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 6-OHDA; 6-hydroxydopamine; AD; ALS; Ac; Ac-Lys; Alzheimer's disease; Amylotrophic Lateral Sclerosis; BBB; BDNF; CBP; DA; DNA; DNA methyltranferases; DNMT; DOPAC; Epigenetics; FDA; Food and Drug Administration; GABA; GDNF; GNAT; GSK-3; Gcn5-related acetyltransferases; HAT; HD; HDAC; HDACI; HDM; HMT; HPLC; HSP; HVA; Histone deacetylase; Histone deacetylase inhibitor; Huntington's disease; LPS; LSD; Lys; MAO; MOZ Ybf2/Sas3 Sas2 and Tip60; MPP+; MPTP; MTT; MYST; Me; MeCP2; NAD+; Neurodegeneration; Neuroprotection; PD; PE; Parkinson's disease; S-adenosyl-homocysteine; S-adenosyl-methionine; SAH; SAHA; SAM; SCFA; SIR2; SNpc; SOD; Substantia Nigra pars compacta; TH; TSA; acetyl; acetyl-lysine; blood brain barrier; brain derived neurotrophic factor; deoxyribonucleic acid; dopamine; glial derived neurotrophic factor; glycogen synthase kinase 3; heat shock protein; high performance liquid chromatography; histone acetyltransferases; histone deacetylase; histone deacetylase inhibitor; histone demethylases; histone methyl-transferases; homovanillic acid; lipopolysaccharide; lysine; lysine-specific histone demethylase; methyl; methyl-CpG binding protein 2; monoamine oxidase; nicotinamide adenine dinucleotide; p300/CREB binding protein; phycoerythrin; qRT-PCR; quantitative real time polymerase chain reaction; short chain fatty acid; silent information regulator 2; suberoylanilide hydroxamic acid; superoxide dismutase; trichostatin A; tyrosine hydroxylase; α-synuclein; αSyn; γ-Aminobutyric acid