Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases

Sharma, Saurabh; Sarathlal, K C; Taliyan, Rajeev

doi:10.2174/1871527317666181004155136

Cited by 41 publications

(31 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Their results highlighted the role of the epigenome in pathological disruptions of the neural circuits [27]. Additionally, the imbalance in histone acetylation levels and consequently the dysfunction in transcription have been associated with a wide variety of NDDs [28]. In vitro and in vivo animal models and post-mortem analysis of brains derived from NDDs patients reported overexpressed level of histone deacetylases (HDACs), thus encouraging new therapeutic approaches in this direction [29][30][31].…”

Section: Mirnas As Pharmacoepigenomic Targets For Nddsmentioning

confidence: 99%

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Nuzziello

Ciaccia

Liguori

2019

Cells

View full text Add to dashboard Cite

Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

show abstract

Section: Mirnas As Pharmacoepigenomic Targets For Nddsmentioning

confidence: 99%

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Nuzziello

Ciaccia

Liguori

2019

Cells

View full text Add to dashboard Cite

show abstract

“…The work developed by Hu et al 173 reports the development of new HDAC6 selective inhibitors based on the structure of the antioxidant small molecule ebselen (28). The study was carried out through the evaluation of several linkers to incorporate the hydroxamic acid group in the structure of ebselen (28), in which the benziso-selenazol-3(2H)-one moiety could serve as a cap group. As a consequence, they discovered analog 29, a far more potent HDAC6 inhibitor (IC 50 = 0.037 µM) than its precursor (IC 50 = 11.5 µM) ( Figure 15).…”

Section: Hdacis As a Starting Point To Design Mtdls For Ndsmentioning

confidence: 99%

“…173 Additionally, the authors evaluated the free oxygen radical scavenging ability of 29 (ORAC-FL = 2.2), which was superior to that displayed by ebselen (28) (ORAC-FL = 0.7), and its glutathione peroxidase-like activity using different peroxides, which was quite similar to that of the reference compound. Cellular evaluations of the protective effect of 29 on H 2 O 2 -induced PC12 cell damage indicated that the protective effect of this compound is more potent than that of ebselen (28) alone or when the HDAC6 selective inhibitor tubastatin A (HDAC6 IC 50 = 0.020 µM) was used. 173 GSK-3β is considered a very promising target in AD-related diseases with the modulation of tau phosphorylation.…”

Section: Hdacis As a Starting Point To Design Mtdls For Ndsmentioning

confidence: 99%

“…Given the importance and urgency of the development of new drugs to address CNS-related diseases, this review is focused on the applicability of HDACis to the treatment of different NDs. The use of HDACis for the treatment of noncancer diseases has been recently highlighted from a perspective regarding the treatment of some rare 27 and neurodegenerative 28,29 diseases. In the manuscript by Brindisi et al, 27 HDAC6 was focused on as a biomarker of Rett syndrome and as a potential therapeutic target for novel drug candidates due to its activity on nonhistone proteins, such as α-tubulin, heat shock protein 90 (HSP90), ubiquitin, and tau; in the mini-review of De Simone and Milelli, 29 the applicability of HDACis as multitarget ligands for the specific treatment of AD was discussed.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

Rodrigues

Pinheiro

Sagrillo

et al. 2020

Medicinal Research Reviews

View full text Add to dashboard Cite

Despite the applicability of histone deacetylase inhibitors (HDACis) for cancer treatment, several works in the literature have shown that these inhibitors can be used in several other diseases, such as neurodegenerative diseases (NDs). This review begins by discussing the signaling pathways of HDACs, focused on the context of NDs, presenting a discussion about the pharmacophoric features of HDACis and crystal structure analysis and discussing interesting case studies from the literature about the development of HDACis. Additionally, a discussion about the consequences of isoform-selective inhibition vs pan-HDACis on neurotoxic effects and clinical trial investigations of HDACis for NDs is also presented.

show abstract

“…Since then a large number of studies have demonstrated the ability of structurally distinct HDAC inhibitors to protect in diverse cell culture, invertebrate, and mammalian models of neurodegenerative conditions. 17,38–40 However, because these pharmacological inhibitors are generally non-selective with respect to the HDAC family, the identity of the specific HDAC(s) that trigger neurodegeneration and that are targeted by the inhibitors to afford protection has been unresolved. A growing and compelling body of evidence points to HDAC3 being a particularly important player in the promotion of neurodegeneration in a variety of disease models.…”

Section: Hdac3 As a Key Contributor To Neurodegenerative Diseasementioning

confidence: 99%

Histone deacetylase-3: Friend and foe of the brain

D’Mello¹

2020

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Histone deacetylases (HDACs) are a family of enzymes that deacetylate histones as well as a large number of other nuclear, cytoplasmic, and mitochondrial proteins. The deacetylation of histones transforms chromatin to a transcriptionally repressed state, whereas deacetylation of other cellular proteins regulates their functional activity through modulation of subcellular location, their interaction with other proteins, and in the case of transcription factors, their DNA-binding ability. A compelling body of evidence derived from the utilization of pharmacological inhibitors indicates that histone deacetylases are important regulators of brain development as well as the pathogenesis of neurodegenerative diseases. However, because most of the pharmacological inhibitors used are non-selective with regard to the different members of the HDAC family, the significance of individual HDAC proteins to brain development and degeneration has been difficult to delineate. This review focuses on HDAC3. Experiments conducted using more recently developed isoform selective inhibitors and molecular genetic approaches demonstrate that HDAC3 regulates different steps of neurodevelopment, including neurogenesis, gliogenesis, glial cell fate determination, and the myelination of oligodendrocytes and Schwann cells. However, specific posttranslational modifications and alterations in its binding partners transform HDAC3 from a protein that is beneficial to the brain to one that is neurotoxic. The role of HDAC3 in the promotion of neurodegeneration and the inhibition of recovery after nerve injury is reviewed. The role of HDAC3 in the regulation of memory in the adult and aging brain is also described. Impact statement Brain development and degeneration are highly complex processes that are regulated by a large number of molecules and signaling pathways the identities of which are being unraveled. Accumulating evidence points to histone deacetylases and epigenetic mechanisms as being important regulators of these processes. In this review, we describe that histone deacetylase-3 (HDAC3) is a particularly crucial regulator of both neurodevelopment and neurodegeneration. In addition, HDAC3 regulates memory formation, synaptic plasticity, and the cognitive impairment associated with normal aging. Understanding how HDAC3 functions contributes to the normal development and functioning of the brain while also promoting neurodegeneration could lead to the development of therapeutic approaches for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.

show abstract

Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases

Cited by 41 publications

References 70 publications

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

Histone deacetylase-3: Friend and foe of the brain

Contact Info

Product

Resources

About