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Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition.
Neurosci Lett. 2018 02 14; 666:48-57.NL

Abstract

Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of dopaminergic neurons and reduced activation of microglial cells. Taken together, here we demonstrate that histone acetylation is disease-dependently altered in PD, likely due the effects of dopaminergic neurodegeneration and microglial infiltration; yet SIRT 2 remains relatively unaltered with disease. Given the stable nature of SIRT 2 expression with disease and the effects of SIRT 2 inhibitor treatment on degenerating dopaminergic neurons and activated microglia detected in vitro, SIRT 2 inhibitors warrant further investigation as potential therapeutics for the treatment of the PD.

Authors+Show Affiliations

UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, 72 Huntley Street, London, WC1E 6DD, UK; 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.harrison@ucl.ac.uk.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.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.

Pub Type(s)

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

Language

eng

PubMed ID

29273397

Citation

Harrison, Ian F., et al. "Pathological Histone Acetylation in Parkinson's Disease: Neuroprotection and Inhibition of Microglial Activation Through SIRT 2 Inhibition." Neuroscience Letters, vol. 666, 2018, pp. 48-57.
Harrison IF, Smith AD, Dexter DT. Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition. Neurosci Lett. 2018;666:48-57.
Harrison, I. F., Smith, A. D., & Dexter, D. T. (2018). Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition. Neuroscience Letters, 666, 48-57. https://doi.org/10.1016/j.neulet.2017.12.037
Harrison IF, Smith AD, Dexter DT. Pathological Histone Acetylation in Parkinson's Disease: Neuroprotection and Inhibition of Microglial Activation Through SIRT 2 Inhibition. Neurosci Lett. 2018 02 14;666:48-57. PubMed PMID: 29273397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition. AU - Harrison,Ian F, AU - Smith,Andrew D, AU - Dexter,David T, Y1 - 2017/12/19/ PY - 2017/09/11/received PY - 2017/12/17/revised PY - 2017/12/18/accepted PY - 2017/12/24/pubmed PY - 2018/12/12/medline PY - 2017/12/24/entrez KW - Histone deacetylase inhibitor KW - Microglia KW - Neurodegeneration KW - Neuroprotection KW - Parkinson’s disease KW - SIRT 2 SP - 48 EP - 57 JF - Neuroscience letters JO - Neurosci Lett VL - 666 N2 - Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of dopaminergic neurons and reduced activation of microglial cells. Taken together, here we demonstrate that histone acetylation is disease-dependently altered in PD, likely due the effects of dopaminergic neurodegeneration and microglial infiltration; yet SIRT 2 remains relatively unaltered with disease. Given the stable nature of SIRT 2 expression with disease and the effects of SIRT 2 inhibitor treatment on degenerating dopaminergic neurons and activated microglia detected in vitro, SIRT 2 inhibitors warrant further investigation as potential therapeutics for the treatment of the PD. SN - 1872-7972 UR - https://www.unboundmedicine.com/medline/citation/29273397/Pathological_histone_acetylation_in_Parkinson's_disease:_Neuroprotection_and_inhibition_of_microglial_activation_through_SIRT_2_inhibition_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3940(17)31010-8 DB - PRIME DP - Unbound Medicine ER -