Trends in Neurosciences
ReviewMultiple roles of HDAC inhibition in neurodegenerative conditions
Introduction
Acetylation and deacetylation of histone proteins associated with chromatin plays a pivotal role in the epigenetic regulation of transcription and other functions in cells, including neurons 1, 2, 3, 4. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the acetylation and deacetylation, respectively, of histone proteins at Lys (K) residues. The interplay between HATs and HDACs alters the net balance of histone acetylation levels, thereby remodeling chromatin structure (Figure 1). In general, an increase in protein acetylation at histone-tails results in a more open and relaxed chromatin conformation, thus facilitating transcription factor interaction with specific gene promoters and activating gene expression. HDACs often function as a component of the transcriptional repressor complex to silence gene expression and induce chromatin compaction through histone protein deacetylation. Accordingly, HDAC inhibition shifts the balance towards enhanced histone acetylation, chromatin relaxation and gene expression.
Imbalance between the activities of HATs and HDACs could lead to disease states. For example, mutation and loss of activity of the HAT, cyclic AMP response element binding protein (CREB)-binding protein (CBP), is causative for Rubinstein–Taybi syndrome, a developmental disorder characterized by mental retardation [5]. In addition to histones, HATs and HDACs also use a number of non-histone proteins as their substrates, notably tubulin and transcription factors such as the tumor suppressor p53, Sp1, Smad7, CREB, the pleiotropic transcription factor NF-κB, and signal transducers and activators of transcription-1 (STAT-1) (reviewed in Refs. 4, 6). In this article we first briefly describe the classification and isoforms of HDACs and the properties of a number of isoform-nonselective and more selective HDAC inhibitors. We then review the current research using various HDAC inhibitors in cellular and animal models of neurodegenerative diseases. The beneficial effects and potential caveats of these studies are discussed. Finally, proposed future directions are addressed.
Section snippets
HDACs and HDAC inhibitors
HDAC enzymes are evolutionarily conserved among many species. In humans, HDAC enzymes can be divided into four major classes based on their homology to yeast HDACs (reviewed in Refs. 7, 8). Class I HDACs include HDAC1, 2, 3 and 8; these are related to the yeast enzyme Rpd3. Class II HDACs include HDAC4, 5, 6, 7, 9 and 10, and are related to the yeast protein HDA1; class II HDACs are further divided into two subclasses – IIa (HDAC4, 5, 7 and 9) and IIb (HDAC6 and 10) – according to their
Neuroprotection by HDAC inhibition in cellular models
HDAC inhibition has neuroprotective effects in both in vivo and in vitro models of brain disorders. One pioneering study noted that levels of the HATs CBP/p300 and histone protein acetylation were decreased during apoptosis induced by potassium deprivation of cultured primary cerebellar granule cells, and during signal activation of β-amyloid precursor protein (APP) in cultured primary cerebral cortical neurons from rodents [21]. Moreover, overexpression of CBP/p300 protected these neurons from
Stroke
Stroke, an acute neurological/neurodegenerative disease, is the third leading cause of death in the USA. Most stroke cases are caused by cerebral ischemia. In a middle cerebral artery occlusion (MCAO) stroke model, reduced bulk histone acetylation was found at Lys residues in the ischemic brain of rats or mice; these changes were restored by treatment with HDAC inhibitors, with a concomitant decrease in infarct volume 41, 42, 43. In a rat MCAO model, Chuang and colleagues showed that
Conclusions and future directions
Accumulating evidence supports the notion that histone hypoacetylation and transcriptional dysfunction are involved in a large number of neurodegenerative conditions in vivo and in vitro. In most cases treatment with class I and II HDAC inhibitors normalizes these deficiencies and protects against neurodegeneration. Multiple genes have been identified that are regulated by HDAC inhibition and are involved in neuroprotection and neurotrophicity (Figure 2). HDAC inhibition was found to induce
Acknowledgements
This work was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH). We thank Jau-Shyong Hong and his colleagues at the National Institute of Environmental Health Sciences (NIEHS), NIH, for their collaboration. The critical comments of Li-Kai Tsai and Zhifei Wang (Molecular Neurobiology Section, NIMH, NIH) and the editorial assistance of Peter Leeds (NIMH) and Ioline Henter (NIMH) are appreciated. We also wish
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