Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases.
Histone acetylation is the modification that is best understood and most tightly associated with synaptic plasticity and memory formation. The dysregulation of histone acetylation has been linked to the memory impairments that are associated with neurodegenerative diseases.
Emerging evidence indicates that changes in the DNA methylation status of synaptic plasticity-associated and memory-associated genes can be rapid and reversible. Members of the DNA methyltransferase (DNMT) family promote the rapid methylation and silencing of these genes, whereas the ten-eleven translocation (TET) proteins (TET1, TET2 and TET3) promote the demethylation and activation of genes that are crucial for synaptic plasticity, memory acquisition and storage.
Although neurodegenerative disorders differ in their underlying causes and pathophysiologies, many involve the dysregulation of restrictive element 1-silencing transcription factor (REST), which acts via epigenetic mechanisms to regulate gene expression.
Polycomb proteins orchestrate the epigenetic remodelling and silencing of genes that are involved in neuronal death, thereby enabling neurons to survive the hypoxia that is associated with ischaemic stroke.
Emerging evidence implicates non-coding RNAs, such as microRNAs and long non-coding RNAs, in the epigenetic remodelling of target genes that are involved in neurodegeneration.
Although the past decade has witnessed the development of new chromatin-modifying drugs and their advance into clinical trials in patients with brain disorders, there remains the persisting challenge of developing drugs that can penetrate the blood–brain barrier and ameliorate neurodegeneration and cognitive deficits with high specificity and minimal toxicity.
Epigenetic mechanisms — including DNA methylation, histone post-translational modifications and changes in nucleosome positioning — regulate gene expression, cellular differentiation and development in almost all tissues, including the brain. In adulthood, changes in the epigenome are crucial for higher cognitive functions such as learning and memory. Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases. Although these disorders differ in their underlying causes and pathophysiologies, many involve the dysregulation of restrictive element 1-silencing transcription factor (REST), which acts via epigenetic mechanisms to regulate gene expression. Although not somatically heritable, epigenetic modifications in neurons are dynamic and reversible, which makes them good targets for therapeutic intervention.
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The authors acknowledge all the authors whose valuable work they could not include owing to the limited number of citations allowed. This work was supported by US National Institutes of Health grants NS046742, MH092877and HD083828; a generous grant from the F. M. Kirby Foundation and a National Alliance for Research on Schizophrenia and Depression (NARSAD) Distinguished Investigator Grant to R.S.Z.; and American Heart Association Scientist Development Grant 16SDG31500001 and NARSAD Young Investigator Grant 25369 to J.-Y.H. R.S.Z. is the F. M. Kirby Chair in Neural Repair and Protection.
The authors declare no competing financial interests.
- Histone post-translational modifications
Covalent modifications of histone proteins, including methylation, phosphorylation, acetylation, ubiquitylation and sumoylation.
The basic building unit of chromatin. It comprises 147 bp of DNA wrapped around a histone octamer that contains two molecules of each of the four histones H2A, H2B, H3 and H4.
- Long-term potentiation
(LTP). A long-lasting (hours or days) increase in the response of neurons to the stimulation of their afferents following a brief patterned stimulus (for example, a 100 Hz stimulus).
- Contextual fear conditioning
A form of conditioning in which animals associate the conditioning context (the 'neutral' conditioned stimulus) with an aversive stimulus (for example, a footshock).
- Oxidative stress
A disturbance in the pro-oxidant–antioxidant balance in favour of the former, which can lead to cellular damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products and lipid peroxidation products.
- Ubiquitin-based proteasomal degradation
A process that is initiated by a protein complex and is based on ubiquitin, a 76-amino acid protein that forms a covalent link with (and thereby marks) proteins destined for degradation. Proteins tagged by a poly-ubiquitin chain are targeted to the proteasome, which is a large, multimeric, barrel-like complex that degrades proteins by proteolysis.
- Single-nucleotide polymorphisms
(SNPs). A type of genetic variation within a DNA sequence that occurs when a single nucleotide (for example, thymine) replaces one of the other three nucleotides (for example, cytosine).
- RNA-induced silencing complexes
(RISCs). A complex of proteins that is involved in silencing target mRNAs.
- Ingenuity Pathway Analysis
A web-based software application that enables the analysis, integration and understanding of data from gene expression, microRNA, and single-nucleotide polymorphism microarrays; and metabolomics, proteomics and RNA sequencing experiments.
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Hwang, JY., Aromolaran, K. & Zukin, R. The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat Rev Neurosci 18, 347–361 (2017). https://doi.org/10.1038/nrn.2017.46
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