Targeting Huntington’s disease through histone deacetylases

Gray, Steven G.

doi:10.1007/s13148-011-0025-7

Cited by 26 publications

(16 citation statements)

References 276 publications

(317 reference statements)

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“…Many, though not all [55], studies have found that class I/IIa HDAC inhibitors have a beneficial impact on cellular, fly, and rodent models of Parkinson's disease [56][57][58][59][60][61][62][63]. HDAC inhibitors likewise have may have promise in Huntingon's disease, and other disorders caused by polyglutamine expansion in mutant neuronal proteins [64][65][66]. The mutant proteins which drive these disorder act within the nucleus to block histone acetyltransferase activities; hence, HDAC inhibitors can act in a compensatory fashion to restore a more appropriate level of histone acetylation [66][67][68].…”

Section: Ketones Modulate Protein Acetylationmentioning

confidence: 99%

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

2015

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Section: Ketones Modulate Protein Acetylationmentioning

confidence: 99%

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

2015

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“…Although its precise mechanism of action remains unclear it is thought to involve an increase of the neurotransmitter gamma-aminobutyric acid (GABA) [101]. HDAC inhibitors are also being studied as possible treatments for polyglutamine diseases like Huntington's disease [102].…”

Section: Small Moleculesmentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

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“…Several reviews discussed the importance of various HDACs in specific NDs [17,18] and recently, HDAC6 was suggested to be a promising target for some of them [19]. In the present work, we aim at reviewing the published data regarding HDAC6.…”

Section: Introductionmentioning

confidence: 99%

HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

Simões-Pires

Zwick

Nurisso

et al. 2013

Mol Neurodegeneration

262

235

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Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of α-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Hutington’s diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity.

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Targeting Huntington’s disease through histone deacetylases

Cited by 26 publications

References 276 publications

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

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