This Review focuses on the family of histone deacetylases (HDACs) and their regulatory roles in cells with specific application to neurons. It presents a structure–function analysis of four HDAC classes, the NAD+-independent and NAD+-dependent enzymes, subcellular localization, and substrates for deacetylation.
Furthermore, we provide a general overview of HDAC functions in the brain and discuss how HDAC biological functions in the brain may relate to CNS therapeutic intervention.
The application of HDAC inhibitors for the treatment of various CNS disorders has emerged in recent years. Chromatin remodelling and transcriptional modulation may underlie the efficacy of HDAC inhibitors in disease models of Rubinstein–Taybi syndrome, Rett syndrome and fragile X syndrome, motor neuron and polyglutamine diseases, and psychiatric and mood disorders. The effects on transcription are the most established therapeutically beneficial mechanism of HDAC inhibitors; however roles are emerging for acetylation in protein function and clearance.
Pharmacological inhibition of HDAC6 and sirtuin 2 (SIRT2) activities increase acetylation of non-histone substrates, modulating cytoskeleton and microtubule dynamics and protein aggregation, suggesting alternative therapeutic targets for HDAC inhibitors in Huntington's, Alzheimer's, Parkinson's and other protein misfolding diseases. Pharmacological targeting of HDAC6 may also affect autophagy, a cellular pathway responsible for degradation of misfolded and aggregated proteins.
Anti-inflammatory and anti-apoptotic properties of HDAC inhibitors may have broad application in the treatment of a range of CNS disorders, including multiple sclerosis. Research suggesting benefits for HDAC mediated suppression of microglia activation are discussed.
HDAC inhibitors affect cellular metabolic pathways, and more specifically restore the defective cholesterol metabolism in models of Niemann–Pick type C disease. A link between metabolism and ageing and the specific roles for sirtuins in regulating these processes suggests potential therapeutic benefits and is discussed in the context of different disease models.
A summary of the current state of development of HDAC inhibitors and chemical, biochemical and biological properties of these small molecules is provided. The use of HDAC inhibitors as CNS drugs is dependent upon the medicinal chemistry development of next generation HDAC inhibitors and their ability to cross the blood–brain barrier.
Histone deacetylases (HDACs) — enzymes that affect the acetylation status of histones and other important cellular proteins — have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors — which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways — have been beneficial in various experimental models of brain diseases. Although mounting data predict a therapeutic benefit for HDAC-based therapy, drug discovery and development of clinical candidates face significant challenges. Here, we summarize the current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein–Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis.
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We are grateful to M. Maxwell for critical review of this manuscript.
- Chromatin remodelling
Defines effects of epigenetic modifiers on the dynamic state of silent versus active chromatin, which consists of differently packaged histones.
- Nuclear localization signal
An amino-acid consensus within a protein sequence that determines nuclear localization.
- Nuclear export signal
An amino-acid consensus within a protein sequence that determines protein exit from the nucleus.
- S phase
The phase of the cell cycle when DNA is synthesized (replicated).
- Purkinje cells
Large neurons with extensive dendritic arbor in the cerebellar cortex. Patients with spinocerebellar ataxia type 1 (SCA1) or SCA7 manifest cerebellar ataxia with degeneration of Purkinje cells, which is caused by polyglutamine extensions in the SCA1 and SCA7 genes.
- Amyotrophic lateral sclerosis
(ALS). Is the most common form of motor-neuron disease.It is characterized by progressive selective degeneration of motor neurons and is mostly sporadic; however about 20% of familial ALS is caused by mutations in superoxide dismutase 1 (SOD1).
- Spinal and bulbar muscular atrophy
(SBMA). Also known as Kennedy's disease, SBMA is an X-linked genetic disorder caused by a polyglutamine-repeat expansion within the androgen receptor gene.
- R6/2 mouse model of Huntington's disease
First transgenic mouse model of Huntington's disease (HD), which is characterized by short life-span and robust neurological phenotype. The transgene encodes a polypeptide derived from the first exon 1 of the HD gene encoding the polyglutamine expansion. Expression of the transgene causes neurological phenotypes and extensive formation of neuronal inclusions and cytoplasmic aggregates.
Mutations in the α-synuclein gene product, which is of unknown function, have been identified in familial Parkinson's disease (PD). α-synuclein protein readily forms insoluble aggregates, and is thought to have a key role in PD pathology.
- Kynurenine pathway
Pathway leading to tryptophan degradation via a sequence of biochemical reactions and formation of bioactive intermediates such as kynurenic acid.
- Oculopharyngeal muscular dystrophy
An autosomal dominant mutation causing extension of the naturally occurring 10 alanine sequence up to a maximum of 17 alanines, resulting in fibril formation of PABPN1, a nuclear protein, and the development of late-onset muscular dystrophy.
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Kazantsev, A., Thompson, L. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7, 854–868 (2008). https://doi.org/10.1038/nrd2681
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