HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration

Mielcarek, Michał; Landles, Christian; Weiss, Andreas; Bradaı̈a, Amyaouch; Seredenina, Tamara; Inuabasi, Linda; Osborne, Georgina F; Wadel, Kristian; Touller, Chrystelle; Butler, Rachel; Robertson, Janette; Franklin, Sophie A.; Smith, Donna; Park, Larry; Marks, Paul A.; Wanker, Erich E.; Olson, Eric N.; Lüthi-Carter, Ruth; Putten, Herman van der; Beaumont, Vahri; Bates, Gillian P.

doi:10.1371/journal.pbio.1001717

Cited by 149 publications

(157 citation statements)

References 66 publications

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“…Histone deacetylases 1 and 2 usually form a heterodimer in multiprotein chromatin remodeling complexes with other co-factors, such as Sin3a, NuRD and REST/CoREST, which are important both for enzymatic activity and specificity of DNA/chromatin interactions (Dovey et al, 2010;Ji et al, 2014;Jia et al, 2012;Lagger et al, 2002;Mielcarek et al, 2013;Reichert et al, 2012;Trivedi et al, 2007;Tsai and Seto, 2002;Zimmermann et al, 2007). A surprise finding from our study was that Sin3a LOF not only recapitulated many of the defects observed with Hdac1/2 LOF, but led to more profound defects at an earlier stage of lung development.…”

Section: Discussionsupporting

confidence: 47%

Sin3a regulates epithelial progenitor cell fate during lung development

et al. 2017

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Mechanisms that regulate tissue-specific progenitors for maintenance and differentiation during development are poorly understood. Here, we demonstrate that the co-repressor protein Sin3a is crucial for lung endoderm development. Loss of Sin3a in mouse early foregut endoderm led to a specific and profound defect in lung development with lung buds failing to undergo branching morphogenesis and progressive atrophy of the proximal lung endoderm with complete epithelial loss at later stages of development. Consequently, neonatal pups died at birth due to respiratory insufficiency. Further analysis revealed that loss of Sin3a resulted in embryonic lung epithelial progenitor cells adopting a senescence-like state with permanent cell cycle arrest in G1 phase. This was mediated at least partially through upregulation of the cell cycle inhibitors Cdkn1a and Cdkn2c. At the same time, loss of endodermal Sin3a also disrupted cell differentiation of the mesoderm, suggesting aberrant epithelial-mesenchymal signaling. Together, these findings reveal that Sin3a is an essential regulator for early lung endoderm specification and differentiation.

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Section: Discussionsupporting

confidence: 47%

Sin3a regulates epithelial progenitor cell fate during lung development

et al. 2017

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“…14 -3-3 association restricts the binding of HDAC4 to importin-␣, indicating that inhibition of HDAC nuclear import likely occurs via occlusion of the NLS (35). A similar regulatory mechanism has been reported for other proteins, including Cdc25 in Xenopus XTC cells and ATXN1 in neurons (21,124).…”

Section: Hdac5-although Numerous Hdac5supporting

confidence: 57%

“…Huntington's disease is caused by the mis-folding of the huntingtin protein, and its pathology is associated with the formation of both nuclear and cytoplasmic aggregates (160). HDAC4 has emerged as a possible promising target for the treatment of Huntington's disease because of its association with the huntingtin protein and its ability to influence the formation of cytoplasmic aggregates (21). As HDAC4 localization is determined by its phosphorylation status, these signaling pathways could be exploited to promote the nuclear retention of HDAC4 in order to limit the formation of cytoplasmic aggregates associated with Huntington's disease pathogenesis.…”

Section: Hdac5-although Numerous Hdac5mentioning

confidence: 99%

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Post-translational Modifications Regulate Class IIa Histone Deacetylase (HDAC) Function in Health and Disease

Mathias

Guise

Cristea

2015

Molecular & Cellular Proteomics

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Class IIa histone deacetylases (HDACs4, -5, -7, and -9) modulate the physiology of the human cardiovascular, musculoskeletal, nervous, and immune systems. The regulatory capacity of this family of enzymes stems from their ability to shuttle between nuclear and cytoplasmic compartments in response to signal-driven post-translational modification. Here, we review the current knowledge of modifications that control spatial and temporal histone deacetylase functions by regulating subcellular localization, transcriptional functions, and cell cycle-dependent activity, ultimately impacting on human disease. We discuss the contribution of these modifications to cardiac and vascular hypertrophy, myoblast differentiation, neuronal cell survival, and neurodegenerative disorders. Molecular & Cellular

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“…Cyclopropanation of the methyl cinnamate derived from 1 as previously described, 6 followed by deprotonation of the racemic intermediate 2 using LDA (1.1−3 equiv) and quenching with an appropriate electrophile (MeI, CCl 4 or NFSI) 14 afforded the tetrasubstituted cyclopropane. The desired isomer was isolated by flash chromatography.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Luckhurst

Breccia

Stott

et al. 2015

ACS Med. Chem. Lett.

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Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.KEYWORDS: Class IIa HDAC inhibitors, hydroxamic acid, CNS exposure, tetrasubstituted cyclopropane, cyclopropanation, Huntington's disease I nhibition of class IIa HDAC enzymes has been suggested as a therapeutic strategy for a number of indications, including Huntington's disease (HD) and muscular atrophy. Class IIa HDACs are large proteins with multiple functions including transcription factor binding and N-acetyl lysine recognition. 1,2 Of most interest to our laboratory is the role of class IIa HDAC biology in HD, in particular the beneficial effect, which has been observed following HDAC4 genetic suppression. 3−5 Replication of these effects in preclinical models of HD via occupancy of the class IIa HDAC catalytic domain would provide a rationale for small molecule therapy. Currently there are no marketed HDAC class IIa-selective inhibitors, whereas four pan-HDAC inhibitors, vorinostat (SAHA), romidepsin, belinostat, and panobinostat are on the market.Class IIa-selective HDAC inhibitors would represent important tools for elucidating the therapeutic potential of this protein family. We recently reported the structure-based design of trisubstituted cyclopropane class IIa-selective HDAC inhibitors as potential therapeutics in HD. 6 This improved selectivity was driven by exploiting a selectivity pocket ( Figure 1, shown with compound 13) that is not present in the class I HDAC isoforms. This pocket is formed as a consequence of a tyrosine-histidine substitution. 7 We now report the discovery of tetrasubstituted cyclopropane hydroxamic acid class IIa HDAC inhibitors, with additional substitution at C1 (Figure 1). These compounds exhibited improved pharmacokinetic profiles, and so may provide a further means for evaluating efficacy in preclinical in vivo HD disease models.

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HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration

Cited by 149 publications

References 66 publications

Sin3a regulates epithelial progenitor cell fate during lung development

Sin3a regulates epithelial progenitor cell fate during lung development

Post-translational Modifications Regulate Class IIa Histone Deacetylase (HDAC) Function in Health and Disease

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

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