Acetylation, a key post-translational modification (PTM), plays a vital role in modulating cellular functions and responses to both internal and external stimuli by regulating gene expression, signal transduction, and protein trafficking (Drazic et al., 2016; Duan and Walther, 2015). Initially identified on histones in the nucleus, acetylation has since been found on numerous non-histone proteins (Drazic et al., 2016; Narita et al., 2019). In eukaryotic cells, protein acetylation is regulated by histone acetyltransferases (HATs), which transfer acetyl groups to lysine residues, and histone deacetylases (HDACs), which remove acetyl groups (Bertos et al., 2001). HATs and HDACs are classified into five and four categories, respectively, based on similarities in homologous regions and motifs related to acetylation (Fig. 1) (Seto and Yoshida, 2014; Voss and Thomas, 2018).

Class I HDACs, including HDAC1, 2, 3, and 8, are homologous to the yeast Rpd3 protein and are primarily expressed in the nucleus. Class II HDACs comprise HDAC4, 5, 7, and 9 (Class IIa), as well as HDAC6 and 10 (Class IIb), sharing sequence homology with the yeast Hda1 protein and exhibiting nuclear-cytoplasmic shuttling. Class III HDACs, consisting of Sirtuins 1–7, are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases homologous to yeast Sir2. Notably, HDAC11, the sole member of class IV HDACs, shares similarities with the catalytic domains of both class I and class II enzymes (Delcuve et al., 2012; Haberland et al., 2009). HDACs from classes I, II, and IV (HDAC1-11) are zinc-dependent, whereas Sirtuins (SIRT1-7) are NAD+-dependent. These enzymes are pivotal in transcriptional regulation and histone metabolism, with numerous targets involved in processes such as genetic regulation, epigenetic modifications, and carcinogenesis (Egger et al., 2004; Wade et al., 1997).

Numerous studies have examined the specific functions and therapeutic potential of HDACs in developmental processes, neurodegenerative diseases, and various mental disorders within the central nervous system (CNS), including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and epilepsy (Cho and Cavalli, 2014; De Simone and Milelli, 2019; Han et al., 2023; Sharma et al., 2019; Suelves et al., 2017; Wang et al., 2009, 2023). Moreover, HDACs have been implicated in myelination and remyelination following injury in the peripheral nervous system (PNS) (Gomez-Sanchez et al., 2022a). Class I HDACs are predominantly nuclear, leading most research on their functions to focus on epigenetic regulation. In contrast, Class IIb HDACs, particularly HDAC6, are primarily cytoplasmic, with growing interest in their non-histone targets. This review summarizes recent findings on the roles of HDAC6 in both CNS and PNS contexts, highlighting the applications and challenges of using HDAC6 inhibitors (HDAC6is) for treating CNS and PNS disorders. The goal is to deepen our understanding of these neurological conditions and contribute to the development of innovative therapeutic strategies.

This review critically synthesizes the latest research on the dual functions of HDAC6 in both the CNS and PNS, with particular emphasis on the “HDAC6 paradox.” This paradox involves maintaining cytoplasmic proteostasis while simultaneously contributing to epigenetic dysregulation in various neurological disorders. By integrating these two fundamental pathological mechanisms, the review offers a novel framework to better understand disease processes and guide the development of precise therapeutic approaches.