Putting the ‘HAT’ back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions

Basso, Manuela; Mahishi, Lata; Kozikowski, Alan P.; Donohoe, Mary E.; Langley, Brett; Ratan, Rajiv R.

doi:10.1517/13543780902810345

Cited by 69 publications

(58 citation statements)

References 92 publications

(114 reference statements)

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“…HDAC inhibitors prevent neurodegeneration and improve behavioral performance in a variety of in vivo models of neurodegenerative disease (3)(4)(5). But because the inhibitors used so far are not selective, the specific HDAC protein(s) that they inhibit in affording neuroprotection remain to be identified.…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

D’Mello

2011

Journal of Biological Chemistry

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Histone deacetylase (HDAC) 7 is a member of the HDAC family of deacetylases. Although some of the HDAC proteins have been shown to regulate neuronal survival and death, whether HDAC7 has a similar role is not known. In this study, we show that HDAC7 protects neurons from apoptosis. In cerebellar granule neurons (CGNs) primed to undergo apoptosis by low potassium treatment, expression of HDAC7 protein is reduced. Reduced expression is also observed in CGNs induced to die by pharmacological inhibition of the proteasome, in cortical neurons treated with homocysteic acid, and in the striatum of R6/2 transgenic mice, a commonly used genetic model of Huntington disease. Forced expression of HDAC7 in cultured CGNs blocks low potassium-induced death, and shRNA-mediated suppression of its expression induces death in otherwise healthy neurons. HDAC7-mediated neuroprotection does not require its catalytic domain and cannot be inhibited by chemical inhibitors of HDACs. Moreover, pharmacological inhibitors of the PI3K-Akt or Raf-MEK-ERK signaling pathways or that of PKA, PKC, and Ca 2؉ /calmodulin-dependent protein kinase fail to reduce neuroprotection by HDAC7. We show that stimulation of c-jun expression, an essential feature of neuronal death, is prevented by HDAC7. shRNA-mediated suppression of HDAC7 expression leads to an increase in c-jun expression. Inhibition of c-jun expression by HDAC7 is mediated at the transcriptional level by its direct association with the c-jun gene promoter. Taken together, our results indicate that HDAC7 is a neuroprotective protein acting by a mechanism that is independent of its deacetylase activity but involving the inhibition of c-jun expression.Histone deacetylases (HDACs) 2 are the catalytic subunits of multiprotein complexes that deacetylate specific lysines in the tail residues of histones, resulting in the compaction of chromatin into a transcriptionally repressed state (reviewed in Refs. 1, 2). Although best studied for their effects on histones and transcriptional activity, it is now known that HDACs regulate the acetylation status of a number of other non-histone proteins, suggesting complex functions of HDACs (1, 2). The 18 HDACs expressed in mammals have been grouped into four classes. Class I HDACs (HDAC1-3 and HDAC8) are composed primarily of a catalytic domain, expressed ubiquitously, and localize to the nucleus where they serve as transcriptional repressors. Class II HDACs (HDAC4 -7, HDAC9, and HDAC10) are larger proteins with an N-terminal regulatory domain involved in protein-protein interactions. These HDACs are expressed tissue-specifically and can shuttle between the nucleus and the cytoplasm in a phosphorylationdependent manner. HDAC11 is the sole member of the class IV HDAC subfamily. Members of the third class of deacetylases are called sirtuins (Sirt1-7). In contrast to proteins in the other three classes, which are zinc-dependent deacetylases, sirtuins are NAD-dependent enzymes.There is growing consensus that HDACs regulate neuronal survival and that deregulated...

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Section: Discussionmentioning

confidence: 99%

“…[3][4][5]. Protection afforded by nonselective pharmacological inhibitors (inhibiting all HDAC proteins efficiently) in certain in vivo models of neurodegeneration has suggested that the activation of HDACs contributes to the promotion of neuronal death.…”

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confidence: 99%

Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

D’Mello

2011

Journal of Biological Chemistry

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“…Despite decoding chromatin language in pathological conditions or cognitively deficient states, HDAC inhibitors (HDACi) might represent a good therapeutic option, as these compounds induce a histone hyperacetylated state that might compensate for acetylation deficits. HDACi-based therapeutic strategies were first applied to models of polyglutamine (polyQ) diseases, such as Huntington's [8,9] and Kennedy's [10], and then subsequently revealed to be successful to some extent in several other animal models of neurodegenerative disease [5,6,11,12]. Importantly, this strategy has also been successfully applied in animals subjected to experimental brain damage [13,14] and recently shown to improve memory functions in aged mice [15].…”

Section: Introductionmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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“…One general approach of increasing interest to clinical neuroscientists, aided by the molecular and genomic revolutions, is the use of drugs that activate endogenous adaptive programs. Indeed, activators of the Nrf2-mediated antioxidant response (Calkins et al, 2009;Smirnova et al, 2011), peroxisome proliferator-activated receptor g-mediated metabolic adaptation and antiinflammatory programs (Zhao et al, 2006), and histone deacetylases inhibitor-induced neuroprotective and repair cassettes (Sleiman et al, 2009;Langley et al, 2009) are examples of how this general approach has been applied. Excitingly, with each of these targets, there is a clear trajectory toward the human bedside.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

Karuppagounder

Ratan

2012

J Cereb Blood Flow Metab

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A major challenge in developing stroke therapeutics that augment adaptive pathways to stress has been to identify targets that can activate compensatory programs without inducing or adding to the stress of injury. In this regard, hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) are central gatekeepers of posttranscriptional and transcriptional adaptation to hypoxia, oxidative stress, and excitotoxicity. Indeed, some of the known salutary effects of putative 'antioxidant' iron chelators in ischemic and hemorrhagic stroke may derive from their abilities to inhibit this family of iron, 2-oxoglutarate, and oxygen-dependent enzymes. Evidence from a number of laboratories supports the notion that HIF PHD inhibition can improve histological and functional outcomes in ischemic and hemorrhagic stroke models. In this review, we discuss this evidence and highlight important gaps in our understanding that render HIF PHD inhibition a promising but not yet preclinically validated target for protection and repair after stroke.

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Putting the ‘HAT’ back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions

Cited by 69 publications

References 92 publications

Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

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