Multiple roles of HDAC inhibition in neurodegenerative conditions

Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Drive MSC 1363, Bethesda, MD 20892-1363, USA.
Trends in Neurosciences (Impact Factor: 13.56). 09/2009; 32(11):591-601. DOI: 10.1016/j.tins.2009.06.002
Source: PubMed


Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histones and other proteins and in regulating fundamental cellular activities such as transcription. A wide range of brain disorders are associated with imbalances in protein acetylation levels and transcriptional dysfunctions. Treatment with various HDAC inhibitors can correct these deficiencies and has emerged as a promising new strategy for therapeutic intervention in neurodegenerative disease. Here, we review and discuss intriguing recent developments in the use of HDAC inhibitors to combat neurodegenerative conditions in cellular and disease models. HDAC inhibitors have neuroprotective, neurotrophic and anti-inflammatory properties; improvements in neurological performance, learning/memory and other disease phenotypes are frequently seen in these models. We discuss the targets and mechanisms underlying these effects of HDAC inhibition and comment on the potential for some HDAC inhibitors to prove clinically effective in the treatment of neurodegenerative disorders.

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    • "Acetylation of histones generally induces a more permissive (open) state of chromatin and increased gene expression while deacetylation does the reverse (Kimura et al., 2005). In humans and rodents, four major classes of HDACs have been characterized (Chuang et al., 2009). Class I HDACs include HDAC1, 2, 3 and 8. Class II HDACs are divided into class IIa HDACs including HDAC4, 5, 7 and 9, and class IIb enzymes including HDAC6 and 10. "
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    ABSTRACT: Epigenetic mechanisms like altered histone acetylation may have a crucial role in epileptogenesis. In two mouse models of temporal lobe epilepsy (TLE), we investigated changes in the expression of class II histone deacetylases (HDAC), a group of signal transducers that shuttle between nucleus and cytoplasm. Intrahippocampal injection of kainic acid (KA) induced a status epilepticus, development of spontaneous seizures (after 3 days) and finally chronic epilepsy and granule cell dispersion. Expression of class II HDAC mRNAs was investigated at different time intervals after KA injection in the granule cell layers and in sectors CA1 and CA3 contralateral to the site of KA injection lacking neurodegeneration. Increased expression of HDAC5 and 9 mRNAs coincided with pronounced granule cell dispersion in the KA-injected hippocampus at late intervals (14 to 28 days after KA) and equally affected both HDAC9 splice variants. In contrast, in the pilocarpine model (showing no granule cell dispersion) we observed decreases in the expression of HDAC5 and 9 at the same time intervals. Beyond this, striking similarities between both TLE models such as fast decreases in HDAC7 and 10 mRNAs during the acute status epilepticus were observed, notably also in the contralateral hippocampus not affected by neurodegeneration. The particular patterns of HDAC mRNA expression suggest a role in epileptogenesis and granule cell dispersion. Reduced expression of HDACs may result in increased expression of pro- and anticonvulsive proteins. On the other hand, export of HDACs from the nucleus into the cytoplasm could allow for deacetylation of cytoplasmatic proteins involved in axonal and dendritic remodeling, like granule cell dispersion. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2015 · Journal of Neurochemistry
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    • "In humans and rodents, multiple HDAC enzymes have been identified. Based on their homology to yeast histone deacetylases they are divided into four major classes (Chuang et al., 2009). Class I HDACs include HDAC1, 2, 3 and 8. Class II HDACs comprise HDAC4, 5, 6, 7, 9 and 10. "
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    ABSTRACT: A prominent role of epigenetic mechanisms in manifestation of epilepsy has been proposed. Thus altered histone H3 and H4 acetylation has been demonstrated in experimental models of temporal lobe epilepsy (TLE). We now investigated changes in the expression of the class I and class IV histone deacetylases (HDAC) in two complementary mouse TLE models. Unilateral intrahippocampal injection of kainic acid (KA) induced a status epilepticus lasting 6 to 24 h, development of spontaneous limbic seizures (2 to 3 days after KA injection) and chronic epilepsy, as revealed by telemetric recordings of the EEGs. Mice were killed at different intervals after KA injection and expression of HDAC mRNAs was investigated by in situ hybridization. We observed marked decreases in the expression of HDACs 1, 2 and 11 (by up to 75%) in the granule cell and pyramidal cell layers of the hippocampus during the acute status epilepticus (2 to 6 h after KA injection). This was followed by increased expression of all class I HDAC mRNAs in all principal cell layers of the hippocampus after 12 to 48 h. In the chronic phase, 14 and 28 days after KA, only modest increases in the expression of HDAC1 mRNA were observed in granule and pyramidal cells. Immunohistochemistry using an antibody detecting HDAC2 revealed results consistent with the mRNA data and indicates also expression in glial cells on the injection side. Similar changes as seen in the KA model were observed after a pilocarpine-induced status epilepticus except that decreases in HDACs 2, 3 and 8 were also seen at the chronic 28 day interval.
    Full-text · Article · Jul 2015 · Experimental Neurology
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    • "(1) Class I HDACs consist of HDACs 1, 2, 3, 8; (2) Class II HDACs further separate into two subclasses, class IIa including HDACs 4, 5, 7, 9 and class IIb HDACs 6, 10; (3) Class III HDACs are named as sirtuins and include SirT1-7, sharing their homology sequence to the yeast Sir2; and (4) Class IV HDACs include only HDAC11 (Chuang et al., 2009 "
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    ABSTRACT: It is becoming more evident that histone acetylation, as one of the epigenetic modifications or markers, plays a key role in the etiology of Alzheimer's disease (AD). Histone acetylases and histone deacetylases (HDACs) are the well-known covalent enzymes that modify the reversible acetylation of lysine residues in histone amino-terminal domains. In AD, however, the roles of these enzymes are controversial. Some recent studies indicate that HDAC inhibitors are neuroprotective by regulating memory and synaptic dysfunctions in cellular and animal models of AD; while on the other hand, increase of histone acetylation have been implicated in AD pathology. In this review, we focus on the recent advances on the roles of histone acetylation covalent enzymes in AD and discuss how targeting these enzymes can ultimately lead to therapeutic approaches for treating AD.
    Full-text · Article · Jun 2015 · Frontiers in Cellular Neuroscience
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