Abstract
Recent studies show that histone deacetylase 6 (HDAC6) has important roles in the human brain, especially in the context of a number of nervous system disorders. Animal models of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders show that HDAC6 modulates important biological processes relevant to disease biology. Pan-selective histone deacetylase (HDAC) inhibitors had been studied in animal behavioral assays and shown to induce synaptogenesis in rodent neuronal cultures. While most studies of HDACs in the nervous system have focused on class I HDACs located in the nucleus (e.g., HDACs 1,2,3), recent findings in rodent models suggest that the cytoplasmic class IIb HDAC, HDAC6, plays an important role in regulating mood-related behaviors. Human studies suggest a significant role for synaptic dysfunction in the prefrontal cortex (PFC) and hippocampus in depression. Studies of HDAC inhibitors (HDACi) in human neuronal cells show that HDAC6 inhibitors (HDAC6i) increase the acetylation of specific lysine residues in proteins involved in synaptogenesis. This has led to the hypothesis that HDAC6i may modulate synaptic biology not through effects on the acetylation of histones, but by regulating acetylation of non-histone proteins.
Highlights
Histone deacetylases (HDACs) and HATs have been studied extensively for their role in regulating chromatin function through acetylation of histone proteins, including in neurons [1,2]
These findings indicate that HDAC6 inhibitors (HDAC6i)-mediated K49 acetylation on β-catenin has an impact on its ubiquitination
Recent studies in animal models as well as in human neurons have led to a better understanding of the role of histone deacetylase 6 (HDAC6) in cellular processes that have important roles in the biology of various neurodevelopmental, neurodegenerative, and neuropsychiatric disorders
Summary
Histone deacetylases (HDACs) and HATs (histone acetyltransferases) have been studied extensively for their role in regulating chromatin function through acetylation of histone proteins, including in neurons [1,2]. Different HDAC isoforms have been shown to control synapse maturation and function in mice with conditional alleles of HDAC isoforms and HDACi induce synaptogenesis in vitro in rodent neuronal cultures [6,7]. Many of these studies have focused on class I HDACs (HDACs 1,2,3) located in the nucleus and most HDACi studied to date have broad selectivity and target multiple HDAC isoforms [8]. CSiinnhciebitthores oarreigdiensaiglndeidscfoorvbeertyterofisotufobramcisneleacstiavitHy,DmAanCy6oifnthheibiinthoirb,ittohresrdeohave been a niunhmibbiterotohefrnHeDwAsCms asllwmelol laetchuilgehserthdaotsehsa. vSiencbeetehne osyringitnhaelsdizisecdovtehryatofshtuobwacibneatstear HisDoAfoCr6m selectivity foinrhHibiDtoAr,Cth6e,reinhcalvuedbineegnsaomnuemwbeirthofbnreawinsbmiaol-lamvoalielacublielsittyha[t11h–av2e2]b(eTenabslyen1th)e. sFizoerdtthheatHshDoAwC6 inhibitor AbCetYte-r73is8o,fomrmicesetlreecatitveidtyfoforr2H1DdAayCs6,reinsculultdeidnginsoamberawinit–hpblraasimn baiora-atvioaiolafb~il1it.y4 [w11h–i2l2e]t(rTeaabtlme e1n).t for 90 days sFhoorwtheedHbDraAiCn6–pinlhaisbmitoarrAatCioY-o73f8~, 2m.3ice[2t3re].atTedhefobrr2a1indabyisor-easvualtieladbiinliatybroafinb–apvlaasrmosatraattiwo aosf ~s1h.4own through thwbaehviralaerdotsirtoeaactthmewemansticfasolhros9yw0nndthateyhssriossuhogofhw[e1td8h]ebFrarbainad–viopaclrahosemsmtaaictraaaltniosdyonthfthe~e2ds.3iesm[2o3of]n. s[T1thr8ae] tbiForanibnoafvbauiorpo-astvataaktielaaabnnilddityrtheotefention of the cdoemmpoonustnradtioinn tohf eupratatkberaanind rwetietnhtipoentoifmthaegcinomg p[2o0u]n.d in the rat brain with pet imaging [20]
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