Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers

Wagner, Florence F.; Zhang, Y.-L.; Fass, Daniel M.; Joseph, Naima T.; Gale, Jennifer; Weïwer, Michel; McCarren, Patrick; Fisher, Stewart L.; Kaya, Taner; Zhao, Wen-Ning; Reis, Surya A.; Hennig, Krista M.; Thomas, Melvin E.; Lemercier, Bérénice C.; Lewis, Michael C.; Guan, Ji‐Song; Moyer, Mikel P.; Scolnick, Edward M.; Haggarty, Stephen J.; Tsai, Li‐Huei; Holson, Edward B.

doi:10.1039/c4sc02130d

Cited by 89 publications

(87 citation statements)

References 40 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Hdac2 RNAi experiments were complemented by treatment with four small molecule HDAC inhibitors with different specificities: trichostatin A (TSA), a HDAC class I and II inhibitor (Yoshida et al, 1990) (Figure S6A); RGFP966, a HDAC class I inhibitor (Chou et al, 2008) (data not shown); and both BRD4884 and BRD6688, which are specific HDAC2 inhibitors (Wagner et al, 2015) (Figures S5I–S5L). All of these small molecules effectively reduced the expression of neural markers in intact polyps and inhibited head regeneration following decapitation (Figures 5L, S5M and S6B-S6L).…”

Section: Resultsmentioning

confidence: 99%

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

et al. 2017

View full text Add to dashboard Cite

SUMMARY SoxB transcription factors and histone deacetylases (HDACs) are each major players in the regulation of neurogenesis, but a functional link between them has not been previously demonstrated. Here, we show that SoxB2 and Hdac2 act together to regulate neurogenesis in the cnidarian Hydractinia echinata during tissue homeostasis and head regeneration. We find that misexpression of SoxB genes modifies the number of neural cells in all life stages and interferes with head regeneration. Hdac2 was co-expressed with SoxB2 and its down-regulation phenocopied SoxB2 knockdown. We also show that SoxB2 and Hdac2 promote each other's transcript levels, but Hdac2 counteracts this amplification cycle by deacetylating and destabilizing SoxB2 protein. Finally, we present evidence for conservation of these interactions in human neural progenitors. We hypothesize that crosstalk between SoxB transcription factors and Hdac2 is an ancient feature of metazoan neurogenesis and functions to stabilize the correct levels of these multifunctional proteins.

show abstract

Section: Resultsmentioning

confidence: 99%

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

et al. 2017

View full text Add to dashboard Cite

show abstract

“…HDAC inhibitors of this type may have potential for preventing and controlling neurodegeneration and cognitive dysfunction [46]. Provocative recent studies reveal that overactivity of HDAC2 -thought to be typical of Alzheimer's disease [47] -impairs long-term potentiation and synaptic plasticity by down-regulating transcription of numerous proteins, including CREB and brain-derived neurotrophic factor (BDNF), that participate in these processes; conversely, inhibition of HDAC2 reverses cognitive dysfunction in mouse models of Alzheimer's [47][48][49][50][51][52]. Excessive deacetylation of histones may also play a pathogenic role in Parkinson's disease; in this disorder, alpha-synuclein accumulates within the nucleus and binds to histone H3, suppressing its acetylation [53,54].…”

Section: Ketones Modulate Protein Acetylationmentioning

confidence: 97%

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

2015

View full text Add to dashboard Cite

“…Some of those that were developed most recently and are not yet commercialized have better tissue penetration and HDAC1 and HDAC2 selectivity than SAHA (Wagner et al., 2015). We suggest that these compounds hold promise for providing therapeutic benefits in cases of progressive hearing loss caused by gain-of-function mutations in REST .…”

Section: Discussionmentioning

confidence: 99%

Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness

Nakano

Kelly

Rehman

et al. 2018

Cell

View full text Add to dashboard Cite

The DNA-binding protein REST forms complexes with histone deacetylases (HDACs) to repress neuronal genes in non-neuronal cells. In differentiating neurons, REST is downregulated predominantly by transcriptional silencing. Here we report that post-transcriptional inactivation of REST by alternative splicing is required for hearing in humans and mice. We show that, in the mechanosensory hair cells of the mouse ear, regulated alternative splicing of a frameshift-causing exon into the Rest mRNA is essential for the derepression of many neuronal genes. Heterozygous deletion of this alternative exon of mouse Rest causes hair cell degeneration and deafness, and the HDAC inhibitor SAHA (Vorinostat) rescues the hearing of these mice. In humans, inhibition of the frameshifting splicing event by a novel REST variant is associated with dominantly inherited deafness. Our data reveal the necessity for alternative splicing-dependent regulation of REST in hair cells, and they identify a potential treatment for a group of hereditary deafness cases.

show abstract

Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers

Abstract: Kinetically selective inhibitors of HDAC2 enhanced learning and memory in a CK-p25 mouse model of neurodegeneration.

Cited by 89 publications

References 40 publications

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

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

Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness

Contact Info

Product

Resources

About