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      The potential of epigenetic therapies in neurodegenerative diseases

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          Abstract

          Available treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, do not arrest disease progression but mainly help keeping patients from getting worse for a limited period of time. Increasing evidence suggests that epigenetic mechanisms such as DNA methylation and histone tail modifications are dynamically regulated in neurons and play a fundamental role in learning and memory processes. In addition, both global and gene-specific epigenetic changes and deregulated expression of the writer and eraser proteins of epigenetic marks are believed to contribute to the onset and progression of neurodegeneration. Studies in animal models of neurodegenerative diseases have highlighted the potential role of epigenetic drugs, including inhibitors of histone deacetylases and methyl donor compounds, in ameliorating the cognitive symptoms and preventing or delaying the motor symptoms of the disease, thereby opening the way for a potential application in human pathology.

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          Most cited references55

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          The diverse functions of histone lysine methylation.

          Covalent modifications of histone tails have fundamental roles in chromatin structure and function. One such modification, lysine methylation, has important functions in many biological processes that include heterochromatin formation, X-chromosome inactivation and transcriptional regulation. Here, we summarize recent advances in our understanding of how lysine methylation functions in these diverse biological processes, and raise questions that need to be addressed in the future.
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            Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain.

            Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Recovery of learning and memory is associated with chromatin remodelling.

              Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                23 May 2014
                14 July 2014
                2014
                : 5
                : 220
                Affiliations
                Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Pisa, Italy
                Author notes

                Edited by: Anne-Marie Baird, Queensland University of Technology, Australia

                Reviewed by: Chris Anthony Murgatroyd, Manchester Metropolitan University, UK; Yves Renaudineau, Brest University Medical School, France

                *Correspondence: Fabio Coppedè, Department of Translational Research and New Technologies in Medicine and Surgery, Medical School, University of Pisa, Via Roma 55, 56126 Pisa, Italy e-mail: fabio.coppede@ 123456med.unipi.it

                This article was submitted to Epigenomics and Epigenetics, a section of the journal Frontiers in Genetics.

                Article
                10.3389/fgene.2014.00220
                4094885
                25071843
                062e8c3a-189f-4121-a687-27453e5f06a5
                Copyright © 2014 Coppedè.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 April 2014
                : 25 June 2014
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 76, Pages: 8, Words: 6554
                Categories
                Genetics
                Mini Review Article

                Genetics
                alzheimer's disease,parkinson's disease,amyotrophic lateral sclerosis,huntington's disease,dna methylation,histone tail modifications,histone deacetylase inhibitors (hdaci),therapeutic approaches

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