Elsevier

The Lancet Neurology

Volume 8, Issue 11, November 2009, Pages 1056-1072
The Lancet Neurology

Review
Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies

https://doi.org/10.1016/S1474-4422(09)70262-5Get rights and content

Summary

Epigenetic mechanisms such as DNA methylation and modifications to histone proteins regulate high-order DNA structure and gene expression. Aberrant epigenetic mechanisms are involved in the development of many diseases, including cancer. The neurological disorder most intensely studied with regard to epigenetic changes is Rett syndrome; patients with Rett syndrome have neurodevelopmental defects associated with mutations in MeCP2, which encodes the methyl CpG binding protein 2, that binds to methylated DNA. Other mental retardation disorders are also linked to the disruption of genes involved in epigenetic mechanisms; such disorders include alpha thalassaemia/mental retardation X-linked syndrome, Rubinstein-Taybi syndrome, and Coffin-Lowry syndrome. Moreover, aberrant DNA methylation and histone modification profiles of discrete DNA sequences, and those at a genome-wide level, have just begun to be described for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and in other neurological disorders such as multiple sclerosis, epilepsy, and amyotrophic lateral sclerosis. In this Review, we describe epigenetic changes present in neurological diseases and discuss the therapeutic potential of epigenetic drugs, such as histone deacetylase inhibitors.

Introduction

Epigenetics refers to the heritable changes in gene expression that are not due to alterations in DNA sequence;1 these changes could explain many cases in which medical observations confront traditional genetics.2 The most obvious cases involve monozygotic twins. Discordant twins have always been a puzzling situation for biomedical researchers and physicians. These individuals are “natural” clones and are identical at the level of DNA sequence. However, the penetrance of various diseases in these individuals, including neurological disorders, can be different. We have shown that monozygotic twins present with epigenetic differences, which are accentuated by increasing age, less time shared together, and lifestyle differences.3

The recognition of the role of epigenetics in human disease started in oncology, but has now extended to other disciplines such as neurodevelopment and neurodegenerative disorders. There are monogenic syndromes in which a mutation in a single gene can lead to epigenetic dysregulation. For example, one of the most common causes of mental retardation in women is Rett syndrome.4 This syndrome is associated with the disruption of MeCP2 (methyl CpG binding protein 2),5 a protein that binds to methylated DNA. There is also disruption of epigenetic mechanisms in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

In this Review we describe the epigenetic setting that defines healthy cells and also outline the aberrant DNA methylation and histone modification mechanisms caused by mutations in certain genes (ie, epigenetic genes). These defective mechanisms can cause several neurodevelopmental disorders and are involved in neurodegenerative diseases and other neurological pathologies such as multiple sclerosis, epilepsy, and amyotrophic lateral sclerosis. We also discuss the potential translational use of these findings and the possible use of epigenetic therapies.

Section snippets

DNA methylation

DNA methylation is the most widely studied epigenetic mechanism. In eukaryotes, it consists of the covalent addition of a methyl group at the 5-position of cytosines, and it is usually associated with gene silencing. This methylation occurs on cytosines that are followed by guanines (CpG dinucleotides). In the human genome, CpG dinucleotides are generally concentrated in regions called CpG islands, which are preferentially located in promoter regions and usually do not contain 5-methylcytosines.

Epigenetic changes in human diseases: cancer

The large amount of data accumulated in the past 25 years of research in cancer epigenetics2, 30, 31 could be an excellent starting point to a better understanding of neurological diseases where similar mechanisms could be involved (Figure 1, Figure 2).

Both genetic and epigenetic alterations contribute to cancer initiation and progression.30, 31, 32 The epigenetic features of cancer that have been mostly studied are changes in DNA methylation. One of the first epigenetic alterations found in

Epigenetic genes and neurodevelopmental disorders

Mutations in genes can cause epigenetic dysfunction that lead to certain neurodevelopmental disorders. Some altered epigenetic patterns are directly associated with the presence of a mutation in an epigenetic gene involved in a neurodevelopmental disorder. Some of these genetic syndromes that often cause mental retardation in children are discussed in this section.

Epigenetic changes in neurodegenerative disorders

In this section, we focus on the emerging evidence linking DNA methylation and histone modification defects to the progression of neurodegenerative disorders. The most relevant DNA methylation changes observed between normal and disease-associated tissue, gain (hypermethylation) or loss (hypomethylation), that might be used as biomarkers for each disorder or as targets for DNA-demethylating drugs are provided in table 1. The changes in the post-translational chemical modifications of histones,

Epigenetic changes in other neurological diseases

Epigenetic alterations have also been described in several other major neurological pathologies, such as spinal muscular atrophy, Friedreich's ataxia, adrenoleukodystrophy, and imprinting disorders such as the Angelman syndrome and Prader-Willi syndrome.28, 29 In this section we focus on the epigenetic changes present in multiple sclerosis, epilepsy, and amyotrophic lateral sclerosis as translational examples. We selected these diseases because of availability of data describing epigenetic

Epigenetic drugs for neurological diseases

Two main epigenetic treatments are currently worth consideration: DNA-demethylating drugs and HDAC inhibitors. The most promising results obtained by use of these drugs are summarised in table 315, 24, 25, 26, 27, 168, 169, 170 and shown in figure 2. Although DNA-demethylating drugs could be suitable for several neurodegenerative and neurodevelopmental diseases, such as fragile X syndrome,171 more effort has been devoted to research with histone deacetylase (HDAC) inhibitors. Studies in the

Conclusions

Cancer researchers first revealed the contribution of epigenetic disruption to human disease, but neurological diseases are being increasingly characterised in this context. One of the breakthrough observations was the discovery that several forms of mental retardation were associated with germline mutations in epigenetic genes such as MeCP2, ATRX, or CBP. From that point on, results from the first preliminary studies of DNA methylation and histone modification profiles in more common

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the search terms “epigenetics”, “DNA methylation”, “histone”, “neurodegenerative”, “Rett syndrome”, “Rubinstein-Taybi syndrome”, “Coffin-Lowry syndrome”, “ATRX syndrome”, “ICF syndrome”, “Alzheimer's disease”, “Parkinson's disease”, “Huntington's disease”, “multiple sclerosis”, “epilepsy”, “amyotrophic lateral sclerosis”, “Friedreich's ataxia”, “multiple sclerosis”, “spinal motor atrophy”, and

References (184)

  • M Esteller

    Relevance of DNA methylation in the management of cancer

    Lancet Oncol

    (2003)
  • M Chahrour et al.

    The story of Rett syndrome: from clinic to neurobiology

    Neuron

    (2007)
  • D del Gaudio et al.

    Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

    Genet Med

    (2006)
  • J Tao et al.

    Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation

    Am J Hum Genet

    (2004)
  • LS Weaving et al.

    Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation

    Am J Hum Genet

    (2004)
  • JH Roelfsema et al.

    Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease

    Am J Hum Genet

    (2005)
  • E Kalkhoven

    CBP and p300: HATs for different occasions

    Biochem Pharmacol

    (2004)
  • RJ Gibbons et al.

    Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome)

    Cell

    (1995)
  • LA Baker et al.

    PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks

    Mutat Res

    (2008)
  • AP Feinberg

    Phenotypic plasticity and the epigenetics of human disease

    Nature

    (2007)
  • MF Fraga et al.

    Epigenetic differences arise during the lifetime of monozygotic twins

    Proc Natl Acad Sci USA

    (2005)
  • M Esteller

    Rett syndrome: the first forty years: 1966–2006

    Epigenetics

    (2007)
  • RE Amir et al.

    Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

    Nat Genet

    (1999)
  • A Bird

    DNA methylation patterns and epigenetic memory

    Genes Dev

    (2002)
  • W Reik et al.

    Epigenetic reprogramming in mammalian development

    Science

    (2001)
  • TM Edwards et al.

    Environmental exposures and gene regulation in disease etiology

    Cien Saude Colet

    (2008)
  • TH Bestor

    The DNA methyltransferases of mammals

    Hum Mol Genet

    (2000)
  • M Fatemi et al.

    MBD family proteins: reading the epigenetic code

    J Cell Sci

    (2006)
  • L Lopez-Serra et al.

    Proteins that bind methylated DNA and human cancer: reading the wrong words

    Br J Cancer

    (2008)
  • S Al-Mahdawi et al.

    The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues

    Hum Mol Genet

    (2008)
  • J Hauke et al.

    Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition

    Hum Mol Genet

    (2009)
  • MA Moscarello et al.

    The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis

    Neurochem Res

    (2007)
  • M Esteller

    Cancer epigenomics: DNA methylomes and histone-modification maps

    Nat Rev Genet

    (2007)
  • M Esteller et al.

    Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents

    N Engl J Med

    (2000)
  • ME Hegi et al.

    MGMT gene silencing and benefit from temozolomide in glioblastoma

    N Engl J Med

    (2005)
  • MF Paz et al.

    CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas

    Clin Cancer Res

    (2004)
  • C Gondcaille et al.

    Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator

    J Cell Biol

    (2005)
  • M Rai et al.

    HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model

    PLoS One

    (2008)
  • E Soragni et al.

    Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia

    Nucleic Acids Res

    (2008)
  • M Esteller

    Epigenetics in cancer

    N Engl J Med

    (2008)
  • AP Feinberg et al.

    Hypomethylation distinguishes genes of some human cancers from their normal counterparts

    Nature

    (1983)
  • JF Costello et al.

    Aberrant CpG-island methylation has non-random and tumour-type-specific patterns

    Nat Genet

    (2000)
  • M Esteller et al.

    A gene hypermethylation profile of human cancer

    Cancer Res

    (2001)
  • R Martinez et al.

    A microarray-based DNA methylation study of glioblastoma multiforme

    Epigenetics

    (2009)

  • Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    Nature

    (2008)
  • M Alaminos et al.

    Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma

    J Natl Cancer Inst

    (2004)
  • MF Fraga et al.

    Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer

    Nat Genet

    (2005)
  • MF Fraga et al.

    Towards the human cancer epigenome: a first draft of histone modifications

    Cell Cycle

    (2005)
  • DB Seligson et al.

    Global histone modification patterns predict risk of prostate cancer recurrence

    Nature

    (2005)
  • AL Collins et al.

    Mild overexpression of MeCP2 causes a progressive neurological disorder in mice

    Hum Mol Genet

    (2004)

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