Table 2.
HDAC enzymes and their roles in neurodegenerative disease (NDD).
| HDAC classes | Representative enzymes | Subcellular Localization | Histone substrates | Examples of non-histone substrates | Identified roles in brain | Identified involvement in NDD | Mislocalization in NDD |
|---|---|---|---|---|---|---|---|
| Class I (Ma and Schultz, 2008; Dovey et al., 2010; Yao and Yang, 2011; Lv et al., 2012; Wang et al., 2012; Chakrabarti et al., 2015; Park and Kim, 2020) | HDAC1 | Nucleus | H4 | MEF2, ATM, p53, MeCP2 | Neurogenesis in developing brains (Cunliffe, 2004; Yamaguchi et al., 2005; Ye et al., 2009; Harrison et al., 2011), dendritic growth (Tea et al., 2010) & microglial maturation (Alliot et al., 1999) | AD (Pao et al., 2020), HD (Jia et al., 2012b), FTLD (Pao et al., 2020) | Cytoplasm (Simões-Pires et al., 2013) |
| HDAC2 | Nucleus | H2A/2B, H3,H4 | NF-κB, MeCP. IRS-1 | AD (Pao et al., 2020), HD (Mielcarek et al., 2011), ALS (Janssen et al., 2010) | - | ||
| HDAC3 | Nucleus | H4 | NF-κB, HDAC4, HDAC5, HDAC7, HDAC9, pRb | Regulating neuronal homeostasis (Soriano and Hardingham, 2011; Norwood et al., 2014), axonal regeneration & memory formation (Fischle et al., 2002; McQuown et al., 2011) | AD (Pao et al., 2020), ALS (Janssen et al., 2010), HD (Jia et al., 2012b) | - | |
| HDAC8 | Nucleus/Cytoplasm | H2A/2B | HSP70 | Neuronal differentiation (Katayama et al., 2018) & skull development (Haberland et al., 2009a) | PD (Quan et al., 2021) | - | |
| Class IIa (Yao and Yang, 2011; Wang et al., 2012; Wang Z. et al., 2014; Caslini et al., 2019; Park and Kim, 2020; Wang et al., 2021) | HDAC4 | Nucleus/Cytoplasm | H4 | FOXO, p53, p21, HDAC3, Runx2, MEF2 | Memory formation and synaptic plasticity (Broide et al., 2007; Kim M. S. et al., 2012), Purkinje cell differentiation & postnatal cerebellum development (Majdzadeh et al., 2008) | AD (Chen Y.-A. et al., 2020), PD (Wu et al., 2017), HD (Mielcarek et al., 2011), ALS (Pegoraro et al., 2020), FTLD (Whitehouse et al., 2015) | Cytoplasm (Mielcarek et al., 2013)/Nucleus (Wu et al., 2017) |
| HDAC5 | Nucleus/Cytoplasm | H4 | HDAC3, MEF2, Runx2 | Differentiation of neuronal stem cells (Schneider et al., 2008) | AD (Agis-Balboa et al., 2013), PD (Mazzocchi, 2021), HD (Yeh et al., 2013), ALS (Janssen et al., 2010), FTLD (Whitehouse et al., 2015) | - | |
| HDAC7 | Nucleus/Cytoplasm | H3 | HDAC3, PML, Runx2, MEF2 | Dendric growth, neurogenesis, neuronal protection, & maturation (Lai et al., 2010; Sugo et al., 2010; Ma and D’Mello, 2011) | AD (Lu et al., 2019), PD (Mazzocchi, 2021) | - | |
| HDAC9 | Nucleus/Cytoplasm | H3, H4 | HDAC3, MEF2, CAM | - | |||
| Class IIb (Yao and Yang, 2011; Wang et al., 2012; Park and Kim, 2020) | HDAC6 | Cytoplasm | - | α-tubulin, Cortractin, HDAC11, HSP90, PP1 | Dendritic growth & branching (Kim et al., 2009) | AD (Simões-Pires et al., 2013), PD (Simões-Pires et al., 2013), HD (Simões-Pires et al., 2013), ALS-FTLD (Simões-Pires et al., 2013), CMT (d'Ydewalle et al., 2011) | Perinuclear (Simões-Pires et al., 2013) |
| HDAC10 | Cytoplasm | - | LcoR, and PP1 | Dendric growth, neurogenesis, neuronal protection, and maturation (Lai et al., 2010; Sugo et al., 2010; Ma and D’Mello, 2011) | - | ||
| Class III (Yao and Yang, 2011; Wang et al., 2012; Seto and Yoshida, 2014; Park and Kim, 2020) | SIRT1 | Nucleus/Cytoplasm | H3, H4 | NF-κB, p300, p53, Ku70, PCAF, TIP60 | Neuronal development, axonal growth, regeneration, & neuroprotection (Pandithage et al., 2008; Tiberi et al., 2012; Li X. H. et al., 2013; Kaluski et al., 2017; Sidorova-Darmos et al., 2018; Garcia-Venzor and Toiber, 2021) | AD (Bonda et al., 2011), PD (Li X. et al., 2020), HD (Jęśko et al., 2017), ALS (Outeiro et al., 2008) | Cytoplasm (Zschoernig and Mahlknecht, 2008) |
| SIRT2 | Cytoplasm | H3, H4 | α-tubulin | AD (Jęśko et al., 2017), PD (Outeiro et al., 2007), HD (Outeiro et al., 2007) | - | ||
| SIRT3 | Mitochondria | H4 | Ku70, GDH, SOD2 | AD (Jęśko et al., 2017), PD (Salvatori et al., 2017), HD (Salvatori et al., 2017), ALS (Salvatori et al., 2017) | - | ||
| SIRT4 | Mitochondria | - | GDH | AD (Jęśko et al., 2017), ALS (Körner et al., 2013) | - | ||
| SIRT5 | Mitochondria | - | Cytochrome c, CPS1 | AD (Akter et al., 2021) PD (Maszlag-Török et al., 2021), ALS (Harlan et al., 2019) | - | ||
| SIRT6 | Nucleus | H3 | TNF-α | ALS (Körner et al., 2013) | - | ||
| SIRT7 | Nucleus | H3 | p53 | - | - | ||
| Class IV (Wang et al., 2012; Núñez-Álvarez and Suelves, 2022) | HDAC11 | Nucleus/Cytoplasm | H3, H4 | HDAC6, Cdt1 | Maturation and development of neuronal cells and oligodendrocytes (Liu et al., 2008, 2009) | HD (Kumar et al., 2022), ALS (Janssen et al., 2010) | - |
ATM, Ataxia-telangiectasia-mutated; CAM, calmodulin; CPS1, Carbamoyl phosphate synthetase 1; Cdt1, chromatin licensing and DNA replication factor 1; FOXO, Forkhead box O; GDH, glutamate dehydrogenase; HSP, heat shock protein; IRS, insulin receptor substrate; LcoR, ligand-dependent receptor co-repressor; MeCP, methyl-CpG-binding domain protein; MEF, myocyte enhancer factor; NF-κB, nuclear transcription factor-kappa B; PP1, protein phosphatase, pRb, retinoblastoma protein; Runx, Runt-related transcription factor; SOD, superoxide dismutase; and TNF, tumor necrosis factor.