Unlocking the epigenetic symphony: histone acetylation's impact on neurobehavioral change in neurodegenerative disorders

Abstract

Recent genomics and epigenetic advances have empowered the exploration of DNA/RNA methylation and histone modifications crucial for gene expression in response to stress, aging and disease. Interest in understanding neuronal plasticity's epigenetic mechanisms, influencing brain rewiring amid development, aging and neurodegenerative disorders, continues to grow. Histone acetylation dysregulation, a commonality in diverse brain disorders, has become a therapeutic focus. Histone acetyltransferases and histone deacetylases have emerged as promising targets for neurodegenerative disorder treatment. This review delves into histone acetylation regulation, potential therapies and future perspectives for disorders like Alzheimer's, Parkinson's and Huntington's. Exploring genetic–environmental interplay through models and studies reveals molecular changes, behavioral insights and early intervention possibilities targeting the epigenome in at-risk individuals.

Plain language summary

Scientists have made progress in understanding how our genes and their chemical modifications play a role in how our brains respond to stress, age and diseases. They are particularly interested in how these processes affect the flexibility of our brain circuits, which is important during growth and aging and in conditions like Alzheimer's and Parkinson's. One key area of focus is controlling a specific chemical change called histone acetylation, which tends to go awry in various brain disorders. Researchers are looking at potential treatments that target specific proteins related to this process. This review explores how these chemical changes might be regulated, potential treatments and the future for disorders like Alzheimer's, Parkinson's and Huntington's. By studying the interaction between our genes and the environment, scientists are uncovering changes at the molecular level, gaining insights into behavior and exploring ways to intervene early for people who are at risk.

Tweetable abstract

Unraveling the brain's epigenetic dance: histone acetylation changes play a key role in Alzheimer's, Parkinson's and Huntington's. Explores potential therapeutic avenues and insights into early interventions. #Epigenetics #Neuroscience.

Neurodegenerative disorders (NDs) impose a substantial global burden, leading to disability and mortality [1–3]. These disorders involve the progressive degeneration of neurons, resulting in the loss of neuronal connections and function, ultimately impairing brain activity. Despite extensive research efforts, current strategies for treating degenerative brain diseases are primarily focused on symptom management. This is not surprising, as neurodegeneration often silently progresses over many years before symptoms become apparent. Recent advancements in next-generation sequencing technologies have provided valuable insights into the transcriptomic patterns of human postmortem brain tissues and in vitro and in vivo models of NDs. These investigations have uncovered established neurodegeneration pathways and identified novel targets, including synaptic degeneration, which is prevalent across various NDs and presents several intriguing characteristics. While extensive genetic evaluations have been conducted on large patient populations, a significant proportion of neurodegenerative cases lack identifiable genetic causes [4–6], and only a limited number of studies have identified gene mutations or defective genes associated with neuropathophysiology [4,6–8].

Recognizing the profound impact of environmental variables, such as exposure to toxins, chemicals, nutritional deficiencies, social determinants, substance abuse and alcohol consumption, on neurodegenerative conditions, the significance of epigenetics in these disorders has garnered considerable attention. Recent breakthroughs indicate that targeting epigenetic modifications is a promising avenue for potential pharmaceutical interventions [9–12]. The identification of aberrant epigenetic alterations linked to NDs is receiving growing attention, underscoring the need to explore recent advancements in apprehending the role of epigenetic mechanisms in neurodegenerative disease research.

All cells share the same genetic code, but each cell type regulates its genes differently to maintain its unique physical and biological characteristics according to its specific tissue or organ. This intricate set of regulatory processes is collectively called the epigenome, meaning ‘above the genome’ [13,14]. It encompasses DNA and histone modifications and interacting proteins that package the genome and define a cell's transcriptional program [15,16]. These dynamic epigenetic changes form the foundation of cell function and allow cells to adapt to their environment [17]. Furthermore, disruptions in these epigenetic mechanisms are now recognized as central contributors to various diseases, including NDs [18]. These epigenetic modifications are heritable, and some can be reversed [19,20]. They occur at the molecular level and can be influenced by various adverse factors, such as environmental cues, agents and stress [21,22]. While genetic factors play a crucial role in determining phenotype outcomes, epigenetic changes add a new layer of complexity to our understanding of biology [23]. In many disorders, epigenetics plays a significant role in the onset and progression of the disease, particularly for conditions with unknown causes. Well-established epigenetic mechanisms include DNA methylation, miRNAs and post-translational modification of histone proteins [24–26]. Recent reviews have already delved into broader perspective mechanisms implicated in severe NDs, such as Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD) [27–29]. Consequently, the current review offers a comprehensive overview of the notable advancements in histone acetylation, specifically focusing on its involvement in gene expression alterations associated with NDs. In the following section, recent advancements related to histone protein acetylation in several prominent neurodegenerative conditions and their impact on the progression of NDs are discussed.

Histone acetylation

Histone acetylation constitutes a pivotal chemical modification within the N-terminal region of lysine residues. Each lysine residue holds the potential for mono-, di- or tri-acetylation within histone proteins, giving rise to numerous acetylation combinations. Remarkably, the scope of this modification encompasses over 40 distinct lysine residues within histones, all subject to the transformative influence of acetylation [30]. The field of proteomics has significantly advanced our understanding of protein acetylation, revealing its prevalence on par with phosphorylation. In this realm, many acetylation sites, numbering in the thousands, have been meticulously uncovered [31–33]. The impact of acetylation modification on protein functionality is manifold, orchestrating the regulation of protein stability, enzyme activity and subcellular localization and intricately modulating protein–protein and protein–DNA interactions.

Two primary classes of enzymes play critical roles in regulating acetylation levels within the cell: histone acetyltransferases (HATs), often referred to as the ‘writers’ of histones, and histone deacetylases (HDACs), commonly known as the ‘erasers’ of histones. These enzymes work in tandem to establish a delicate equilibrium of acetylation, serving as pivotal actors in the sophisticated regulatory mechanism that governs gene expression. This fine-tuned balance intricately manages a wide array of physiological processes and the equilibrium of disease states [30]. Distinct combinations of HATs and HDACs elegantly govern various gene promoters’ acetylation status (Figure 1). Extensive investigations spanning large chromosomal domains have illuminated a dynamic and continuous genome-wide flux in acetylation patterns [34,35]. In the realm of transcriptional regulation, histone acetylation and deacetylation exert significant influence by shaping the higher-order structural characteristics of chromatin fibers. Beyond their role in charge neutralization, the acetylation of lysine residues is not limited to altering chromatin structure but also extends to providing specialized binding surfaces that facilitate interactions with both transcriptional repressors and activators [36].

Figure 1. . Histone acetyltransferases enzymatically transfer acetyl groups to core histones, neutralizing the positive charge of lysine residues in the N-termini of histones.

This acetylation modification induces a relaxed chromatin structure, rendering it more accessible to transcription factors and facilitating the activation of gene transcription. However, in numerous neurodegenerative disorders, HAT activity is often compromised. Targeting HAT activators presents a promising avenue for potential therapeutic intervention to reverse suppressed chromatin and gene expression, thereby mitigating the pathogenesis associated with neurodegenerative disorders. Conversely, histone deacetylation, catalyzed by histone deacetylases, typically results in a compact chromatin structure and the repression of gene transcription. Therapeutically, HDAC inhibitors have demonstrated potential by enhancing histone acetylation and promoting gene expression in various neurodegenerative disorders.

HAT: Histone acetyltransferase; HDAC: Histone deacetylase.

Among HATs, three major families are responsible for catalyzing the acetylation of histones, each functioning as multisubunit complexes [37]. These families include P300/CREB-binding protein (P300/CBP), monocytic leukemia zinc finger protein (MYST; Moz, Ybf2, Sas2 and Tip60) and GCN5-related N-acetyltransferase (GNAT) families. The CBP/P300 family of enzymes stands out for its efficiency and relatively lower substrate specificity than other HATs. Studies have demonstrated that recombinant CBP/P300 can acetylate all four histones (H1, H2, H3 and H4) in their global histone form or within nucleosomes [38]. In the case of GNATs, many of these enzymes facilitate the transfer of an acetyl group from acetyl-CoA to the primary amine of the target substrate. This includes histones interacting with P300/CBP, contributing significantly to transcriptional regulation [39]. The MYST family of HATs exhibits diverse biological functions, including activating transcription processes [40].

The discovery of HDAC enzymes, known for their role in transcriptional repression, closely paralleled the identification of HAT enzymes. These HDAC enzymes encompass 18 members, primarily categorized into 4 classes, designated as I, II, III and IV. Class I HDACs, comprising HDAC1, HDAC2, HDAC3 and HDAC8, primarily reside within the cell nucleus. Notably, HDAC1 and HDAC2 are frequently encountered within transcriptional corepressor complexes, such as SIN3A, NuRD and CoREST. On the other hand, HDAC3 is found in distinct complexes, including the silencing mediator of retinoid and thyroid hormone receptor/nuclear receptor corepressor (SMRT/N-CoR). Class II HDACs are divided into subclasses IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and IIb (HDAC6 and HDAC10). Class IIa HDACs are primarily located at the nucleus–cytoplasm interface. In contrast, class IIb HDACs are predominantly situated in the cell cytoplasm. Class III HDACs, also known as sirtuins, encompass members with diverse cellular localizations. This class includes nuclear sirtuins (SIRT1, SIRT2, SIRT6 and SIRT7), mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) and cytoplasmic sirtuins (SIRT1 and SIRT2). Lastly, the class IV HDAC, HDAC11, is predominantly found in the cell nucleus [41–44].

HDAC inhibitors (HDACi) are crucial in modulating gene expression by targeting HDAC isoforms. The inhibition of specific HDAC isoforms increases acetylation levels of histone proteins and other nuclear proteins. This, in turn, promotes gene activation through enhanced accessibility of DNA by RNA Pol II and enables protein–protein interactions between bromodomain-containing proteins and acetyl-lysine residues. HDACi can be natural or synthetic small molecules exhibiting diverse structures, selectivity and biological activities. The pharmacophore of HDACi typically comprises a metal-binding moiety or functional group, a capping group and a linker. The metal-binding group facilitates the catalytic metal binding to the active site of the HDAC. In contrast, the capping group interacts with the amino acids at the lysine binding site. The linker, which structurally resembles the carbon chain in the acetyl-lysine substrate, connects the metal-binding and capping groups, enabling interaction with the HDAC active site [45]. Recent advancements in HDAC-inhibition strategies include alternative approaches focusing on disrupting protein–protein interactions essential for HDAC activity, deviating from the traditional zinc ion chelation at the active site [46]. At the preclinical stage, a noteworthy development in HDACi discovery involves the identification of compounds with an enhanced isoform selectivity profile compared with those currently in clinical development. Despite nonselective HDACi, the discovery of highly selective compounds has become instrumental in gaining insights into the optimal specificity required for addressing NDs [47]. Developing selective HDACi poses several challenges in overcoming specificity and isoform selectivity issues. A significant concern is the lack of specificity associated with HDACi, particularly in achieving selective inhibition of specific isoforms. Additionally, incomplete knowledge exists regarding the off-target actions of HDACi, contributing to uncertainties in their broader effects. Understanding the mechanisms of action and the diverse ways HDACi impact gene expression is a critical topic that demands further exploration. Current research is driven by the pressing need to unravel the intricacies of HDACi actions to design novel reagents with enhanced effectiveness and specificity. Future research efforts are anticipated to contribute to a deeper understanding of the mechanisms underlying HDACi, paving the way for designing more effective and selective therapeutic interventions. As research progresses, it is hoped that the challenges associated with HDACi will be addressed, leading to the development of more targeted and efficacious treatments for various medical conditions.

Neurodegenerative disorders

Numerous vital biological processes in the human brain rely on histone acetylation, including synaptic plasticity, memory formation and consolidation [48]. In the hippocampus, histone acetylation plays a pivotal role in the development of excitatory synapses, essential components of standard forms of synaptic plasticity such as long-term potentiation (LTP) and establishing long-term memory [49]. Extensive research employing animal models has shed light on the significance of histone acetylation in learning, memory and synaptic plasticity. One notable study revealed increased H3 acetylation at the BDNF gene promoter region in the hippocampus of adult mice following contextual fear conditioning, a condition linked to learning and memory impairments [50]. Additionally, histone acetylation appears to be upregulated in regions targeted by the transcription factor NF-κB in genes associated with memory consolidation [51,52]. Intriguingly, adult mice expressing a mutant form of CBP with reduced HAT activity displayed impaired long-term memory consolidation. Remarkably, these impairments were rescued when CBP HAT activity was restored or when HDACi were employed [53]. Furthermore, CBP-mutant mice exhibited impaired LTP and deficits in long-term memory formation, underscoring the critical role of histone acetylation in memory and synaptic plasticity [54,55].

Recent therapeutic interventions have employed HDACi with promising results [47]. HDACi enhance histone acetylation by targeting HDACs, thereby preventing histone deacetylation and facilitating chromatin accessibility, ultimately promoting active gene expression [56]. Genetic factors undeniably have a significant influence on age-associated mechanisms. Nevertheless, they alone cannot account for all the intricate changes observed in organisms as they age. Studies involving twins have shed light on the mechanisms underpinning phenotypic variations in aging that elude simple genetic explanations [57]. These elusive distinctions often stem from epigenetic mechanisms, with histone acetylation modifications as a noteworthy example [48,49]. The intricate interplay between aging and neurodegenerative diseases is well-documented, with conditions like AD, PD and HD exhibiting close associations with epigenetic modifications (Figure 2) [24–26,58–60].

Figure 2. . A prevalent epigenetic mechanism involves modification of histone acetylation, which is intricately linked to genetics, environmental factors, stress and the pathogenesis of age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

Modulation of histone acetylation is a potential avenue for pharmacological intervention, where using HAT activators or HDACi could alleviate pathology associated with these debilitating disorders.

HAT: Histone acetyltransferase; HDACi: Histone deacetylase inhibitors.

Histone acetylation changes in AD

AD is the most prevalent neurodegenerative condition affecting the elderly population worldwide. Clinically, it is characterized by cognitive impairment while pathologically, it is identified by the presence of amyloid-beta (Aβ) plaques derived from amyloid precursor protein (APP), which is encoded by the APP gene. Additionally, intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated forms of a microtubule-associated protein (Tau; encoded by the MAPT gene) contribute to the disease. The accumulation of Aβ is primarily triggered by mutations in genes responsible for APP, PSEN1 and PSEN2. These mutations lead to early-onset AD. Moreover, specific atypical variants in these genes increase the risk of developing late-onset AD.

Significant changes in chromatin structure represent a prominent pathological hallmark in numerous neurodegenerative diseases. In AD, the aberrant processing of APP leads to substantial transcriptional modifications [61,62]. The earliest instance of transcription factors influencing gene expression harkens back to the discovery of ATF-2, which has been associated with early AD pathology [63]. ATF-2 plays a pivotal role in mediating the effects of the cyclic AMP-activated cAMP and PKA-dependent signaling pathway through its binding to the cAMP response element (CRE) DNA sequence. This interaction, in turn, facilitates the transcriptional activation of a substantial array of genes in the brain [64,65]. CBP interacts with a diverse range of transcription factors and components of the RNA Pol II complex, functioning as a coactivator and repressor of transcription. Moreover, CBP's HAT activity contributes to transcription by remodeling chromatin structure [53,54].

In vitro experiments have revealed that the addition of Aβ inhibits CREB phosphorylation and the activation of the CRE-containing BDNF exon III promoters, along with the expression of BDNF exon III mRNA induced by neuronal depolarization [66]. Subsequently, it was demonstrated that Aβ directly affects the cAMP/PKA/CREB signaling pathway, inhibiting LTP in the hippocampus [67]. P300/CREB-binding protein-associated factor (PCAF) regulates gene expression as a transcription coactivator through histone acetylation. Injection of Aβ into P300/CBP-associated factor (PCAF) knockout (KO) mice resulted in resistance to Aβ toxicity and mitigated learning and memory impairment compared with wild-type (WT) littermates [68]. Similarly, PCAF inhibitor (C-30-27) rescued damaged cholinergic systems and cognitive impairments in the Aβ-treated rats [69]. Further, PCAF inhibition improved memory deficits in female 3xTG-AD mice [70]. CREB-regulated transcription coactivator 1 (CRTC1), which plays a pivotal role in linking synaptic activity to gene transcription and is essential for hippocampal-dependent memory, is also disrupted by Aβ [71]. Specifically, Aβ impairs the neuronal expression of CRTC1-dependent genes associated with synaptic plasticity, such as c-fos, Bdnf IV (exon IV) and NR4A2. However, it does not affect Cyr61, a CREB target gene activated independently of CRTC1 [71]. Furthermore, CBP's role extends to the c-fos gene promoter, where it is recruited in an activity-dependent manner. CBP's HAT function becomes indispensable for the expression of the c-fos gene, which is crucial for memory formation and consolidation (Table 1) [52].

Table 1. . Changes in histone acetyltransferase and its activity in Alzheimer's disease models.

Model	Drug	modification	Effect	Refs.
CBP (HAT-) mice		CBP HAT HDACi	LTM in VPC ↓	[53,54]
	TSA		LTM in VPC ↑
cbp+/- mice			Locomotor skills, fear conditioning, LTM, L-LTP ↓	[53,54]
	SAHA	HDACi	L-LTP, contextual fear conditioning ↑
PCAF WT mice	Aβ (25–35)	HAT modulation	CA1 pyramidal cells ↓, oxidative stress, endoplasmic reticulum stress, apoptosis and memory deficits ↑	[68]
PCAF KO mice			Toxicity ↓
BV2 and neuro-2A cells	C-30-27	PACF inhibitor	NF-κB acetylation ↓	[69]
3xTG-AD mice	Embelin	HAT inhibition	Spatial memory deficits ↑	[64]
APPSw,Ind (line J9) & primary neurons APPSw,Ind	TTX	–	CRE transcriptional activity ↓	[71]
3xTg-AD mice	CBP viral delivery	–	Learning and memory ↑	[72]
Rat cerebellar granule neurons	TNF-α	–	Neuron-specific expression of CBP ↑	[73]
PS cDKO mice	–	–	NMDA receptor-mediated responses synaptic levels, αCaMKII, CBP and CREB/CBP target genes ↓	[74]

↓: Decreased; ↑: Increased; αCaMKII: Ca(2+)/calmodulin-dependent protein kinase IIα; Ace: Acetylated; Aβ: Amyloid beta; AD: Alzheimer's disease; CBP: CREB-binding protein; CRE: cAMP response element; CRTC1: cAMP-response element binding protein–regulated transcription coactivator1; H3K9: Histone 3 lysine 27; HAT: Histone acetyltransferase; HDAC: Histone deacetylase; HDACi: Histone deacetylase inhibitors; iPSC: Induced pluripotent stem cell; LTM: Long-term memory; LTP: Long-term potentiation; L-LTP: Late long-term potentiation; NMDA: N-methyl-D-aspartate; PACF: p300/CREB binding protein-associated factor; p-Tau: Phosphorylated Tau; SAHA: Suberoylanilide hydroxamic acid; α; TTX: Tetrodotoxin; VPA: Visual-paired comparison.

In a mouse model of AD, specifically the 3xTG model, researchers observed impaired activity-dependent CREB activation leading to compromised learning and memory. However, it improved learning and memory when they delivered CBP via a viral vector, with no significant alteration in Aβ or Tau pathology. Instead, these cognitive enhancements were associated with increased BDNF [72]. Similarly, in conditional KO mice lacking both PSENs (1 and 2), proteins implicated in AD pathophysiology, there was reduced expression of CBP and CREB/CBP target genes, including c-fos and BDNF. These mice exhibited impaired hippocampal memory and synaptic plasticity [74]. Furthermore, in vivo, preadministration of TNF-α, a substance that preconditions neurons against various toxic insults, including Aβ, in the mouse cortex inhibited Aβ-induced apoptosis and prevented the loss of cholinergic neurons. This protective effect was attributed to the enhancement of neuronal CBP [73]. These findings highlight the importance of enhancing CREB signaling and CBP HAT activity as potential strategies to alleviate memory deficits associated with the loss of CBP function (Table 1).

These observations suggest that transcription factors, acting through histone protein modifications, could serve as mediators facilitating interactions between environmental risk factors and genetics, or they might directly engage with disease-specific pathological elements. A mounting body of evidence indicates that histone acetylation regulated by HDACs holds equal importance in maintaining long-term memory [48,75,76]. For instance, HDACi, such as tyrosine A and sodium butyrate (NaBu), exhibit the capacity to enhance LTP in acute hippocampus (HP) slices and promote memory consolidation during contextual fear conditioning [77,78]. Given that histone acetylation unfolds at various lysine positions in the core histone structure [79], distinct forms of learning might induce specific acetylation patterns at gene promoters. Among different classes of HDACs, HDAC2 has emerged as a negative regulator of memory. Elevation of HDAC2 levels in neurons [80] impairs dendritic synaptic plasticity and memory formation; conversely, deletion of HDAC2 results in memory enhancement. In the context of learning, the Bdnf promoter exhibits responsiveness to changes in histone acetylation. After fear conditioning, a unique acetylation pattern emerges around Bdnf promoters on histones H3 and H4 [81]. Therefore, HDACs play a key role in the homeostasis of protein acetylation in histones and other proteins and in regulating fundamental cellular activities such as transcription. Imbalances in transcription have been shown to contribute to various brain disorders, including NDs.

In addition to reduced CBP HAT activity, it was observed that in AD brains, the protein level of HDAC6, a unique cytoplasmic deacetylase, was significantly enhanced and interacted with a Tau [82]. This finding suggests that HDAC6 likely plays a role in neurodegeneration by coordinating cell responses to abnormal protein aggregation. The APP/PS1 model, which exhibited reduced levels of hippocampal acetylated histone 4 (H4), was rescued by acute administration of HDACi Trichostatin A (TSA) before fear conditioning training. Moreover, TSA rescued HP LTP in slices and contextual freezing performance in APP/PS1 mice [83]. Another HDAC6 inhibitor (ACY-738) significantly rescued AD phenotype in APP/PS1 mice [84]. A different HDAC6 inhibitor (MPT0G211) significantly reduced phosphorylated Tau (p-Tau) and rescued memory impairments in the 3xTg-AD model [85]. These findings suggested the H4 acetylation mechanisms in impaired synaptic and memory function associated with AD. Similarly, chronic administration of sodium valproate, NaBu or vorinostat (suberoylanilide hydroxamic acid; Zolinza; class I HDACi) completely restored contextual memory in APP/PS1 mice [86]. Administration of 4-phenylbutyrate induced clearance of intraneuronal Aβ accumulation, restored dendritic spine densities, plasticity-related proteins and fear learning in the Tg2576 mouse model of AD [87]. Significantly, prolonged treatment with the pan-HDACi NaBu improved associative memory in APP/PS1 mice, even when administered at a very advanced stage of pathology [88]; reduced Aβ accumulation [89] and prevented memory deficits in Tg2576 mice [90]. It also rescued neurodegenerative phenotypes and contextual memory in PS1 and PS2 double-KO mice [91]. The lowered patterns of H3 K18/K23 acetylations were identified by targeted proteomics using LC-MS/MS-tandem-mass-tagging in AD compared with the control brain [92]. Increased HDAC2, H4K12 acetylation and genes associated with synaptic plasticity were also found in CA1 and the entorhinal cortex from animal models and postmortem AD samples [93], the earliest and most vulnerable brain areas in AD [94], critical for learning and memory [95]. In addition, shRNA-mediated knockdown (KD) of HDAC2 reversed the suppressed genes and structural and synaptic plasticity. It ameliorates ND-associated memory deficits [93]. These findings indicate that enhanced HDAC2 may be responsible for the cognitive decline of the human neurodegenerating brain and strongly advocate using HDAC2-selective HDACi to relieve hampered plasticity in AD.

In 3xTg-AD mice compared with control mice, a notable association existed between enhanced H4 acetylation and reduced expression of Bdnf (IV, V and exon IX) genes [96]. Similarly, in postmortem AD brain tissue compared with age- and sex-matched neurologically normal control brain tissue, significant increases in acetylated H3 and H4 levels and total histone H3 and H4 protein levels were observed [97]. In the same AD mice model, the HDAC3 inhibitor RGFP-966 exhibited several beneficial effects, including a reduction in Aβ accumulation, reversal of pathological p-Tau, increased levels of the Aβ degrading enzyme neprilysin in plasma and the rescue of spatial learning and memory impairments [98]. The HDACi sodium valproate also demonstrated potent rescue of spatial and recognition memory deficits in the APP/PS1 mice model [99,100]. Furthermore, a selective HDAC3 inhibitor, BG45, rescued H3K9K14/H3 acetylation levels and reduced Aβ deposition. It also lowered the levels of p-Tau proteins, reduced the number of IBA1-positive microglia (a marker for microglial activation) and GFAP-positive astrocytes, upregulated synaptic proteins, decreased inflammatory cytokine gene expression and promoted neuronal regeneration [101]. Evaluation of changes in H3K9 acetylation in three brain regions of patients with AD revealed enhanced H3K9 acetylation in the cerebellum but reduced levels in the hippocampus compared with elderly controls. These alterations in H3K9 acetylation were associated with abnormal gene expression patterns [102]. In a genome-wide analysis of H3K27 acetylation in three major brain cell types from the hippocampus and dorsolateral prefrontal cortex of subjects with and without AD, microglia-specific gene-regulatory elements were implicated. Microglia exhibited more acetylation changes associated with age than with Aβ load. In contrast, the oligodendrocyte-enriched glial cell population accounted for the most differentially acetylated peaks associated with Aβ load [103]. These findings suggest that oligodendrocyte-enriched glial gene regulation could be a mechanism through which early- and late-onset risk genes exert their effects, highlighting the dysregulation of myelinating processes in AD.

Tyrosine kinase receptor A (TrkA) plays a crucial role in safeguarding cholinergic neurons in AD [104] by regulating vesicle recycling through Rab5-mediated mechanisms [105,106]. Elevating TrkA expression with HDACi, specifically, β-hydroxybutyrate, mitigates the decline in cell vitality and reduction in TrkA expression induced by Aβ. These findings suggest that targeting epigenetic mechanisms and TrkA regulation could offer valuable avenues for future AD treatments. Additionally, β-hydroxybutyrate inhibits increased expression of HDAC1/2/3 and decreases in H3K9 and H4K12 acetylation levels in Aβ-treated cells [107], offering a potential therapeutic avenue for AD. In patients with end-stage AD compared with age-matched controls, alterations in histone acetylation-associated enzymes were observed. Specifically, reduced levels of CBP, PCAF, HDAC1 and HDAC2 were detected in the frontal cortex (F2 area), while in the hippocampus, only HDAC1 and CBP were reduced [108]. In a rat model of diabetes induced by a high-fat diet, hyperacetylation of H3K9 on the CDK5 promoter occurred. This hyperacetylation was driven by the upregulation of GCN5 and was counteracted by the inhibition of GCN5 by MB3. As a result, CDK5 activation was attenuated, leading to reduced levels of p-Tau in the rat brain and an improvement in cognitive impairments [109]. These observations in patients with end-stage AD and a rat model of diet-induced diabetes underscore the relevance of histone acetylation-related enzymes in cognitive function and neuroprotection.

The genome-wide association of H3K9 acetylation alterations in AD mouse models mirrors findings from the dorsolateral prefrontal cortex of 669 human subjects. This alignment suggests that rather than Aβ, Tau primarily drives profound H3K9 acetylation-mediated spatial chromatin remodeling. Importantly, this study implies that genomic H3K9 acetylation changes induced by Tau are early events occurring downstream of pathologic Tau accumulation but preceding the development of NFTs [110]. Genome-wide association studies have revealed that a reduction in Ets family transcription factor (PU.1), a critical factor in the development of myeloid cells and microglia gene expression [111], is linked to a delay in the onset of AD [112]. Moreover, this reduction is associated with microglial genes in innate and adaptive immunity. Notably, vorinostat, an HDACi identified through high-throughput drug screening, has effectively suppressed PU.1 expression in human microglia. These findings suggest the potential therapeutic value of vorinostat, which can suppress PU.1 expression and potentially mitigate microglia-mediated immune responses, including the heightened inflammation observed in AD [111]. In mouse models of AD, a PU.1 specific inhibitor (A11) prevented neuroinflammation, loss of neuronal integrity and AD pathology and rescued cognitive impairments [113]. Similarly, CTCF, an essential protein in genome architecture, controls chromatin structure and gene transcription complexity. In patients with AD, CTCF's binding to genes related to synaptic, cell adhesion and cytoskeleton functions is significantly reduced [114]. Genes with decreased CTCF binding and lower H3K27 acetylation in AD are primarily linked to synaptic organization, suggesting that disrupted chromatin organization may contribute to altered gene expression in AD [114]. These insights offer potential therapeutic avenues for targeting specific histone acetylation- and immune-related mechanisms in AD treatment.

Phosphodiesterases (PDEs) serve as vital mediators for crosstalk between the cGMP and cAMP signaling pathways by regulating the concentration of one cyclic nucleotide, which, in turn, affects the degradation of the other [115]. Particularly, PDE5 assumes a pivotal role in the degradation of cGMP across various tissues, including the brain. The nitric oxide/cGMP/CREB signaling pathway is significant for the learning and memory process [116]. The degradation of cGMP is implicated in the neurodegenerative features of AD, making drugs that inhibit this degradation process highly valuable from a therapeutic perspective [117]. Inhibiting PDE5, similar to the effects seen with vasodilator drugs like Viagra, has shown promise in improving phenotype deficits in AD. Notably, PDE5 inhibition enhances the phosphorylation of CREB, a critical factor in memory formation. Sustained PDE5 inhibition leads to lasting improvements in CREB phosphorylation, cGMP/PKG/pCREB signaling, synaptic function and even the reversal of memory deficits and neuroinflammation, attributed mainly to sustained reductions in Aβ levels [118,119]. Subsequently, the combination of PDE5 inhibition (using tadalafil) with an HDACi (vorinostat) rescued LTP in brain slices [120]. This combination therapy alleviated learning and memory impairments in AD mice [120]. These findings underscore the potential of HDAC and PDE5 inhibitors (Table 2) as a multitarget therapeutic approach for AD treatment, offering synergistic benefits for patients.

Table 2. . Changes in histone deacetylation process in Alzheimer's disease models.

Model	Drug	Modification	Effects	Refs.
APP/PS1 mice	Trichostatin A	Class I and II HDACi	Acetylated H4 levels and contextual freezing performance ↑	[83]
APP/PS1 mice	ACY-738	HDAC6i	Axon transport, acetylated tubulin, contextual fear-associated memory ↑ p-Tau ↓	[84]
3xTg-AD model	MPT0G211	HDAC6i	p-Tau ↓ Acetyl-α-tubulin accumulation ↑	[85]
APPswe/PS1dE9 mice	VPA, NaBu or Vorinostat	Class I HDACi	Histone acetylation ↑ Contextual fear-associated memory ↑	[86]
Tg2576 mice	PBA	Class I HDACi	Aβ ↓ Dendritic spine densities, NR2B ↑	[87]
APPPS1–21 Tg2576 mice hAPPWT-overexpressing mice	NaBu/PBA	Class I HDACi	Associative memory ↑ APP and neuronal loss ↓ Prevented memory deficits ↓	[88–90]
PS1 and PS2 double-KO mice	NaBu	Class I HDACi	Contextual fear memory ↑ Tau hyperphosphorylation ↓	[91]
Adult neuron cells	TSA	Class I and II HDACi	Aβ toxicity ↓ H3 acetylation ↑ BDNF (IV, V and exon IX) ↑	[90]
SK-N-SH cells	Valproic acid	Class I HDACi	Histone acetylation ↑ Cell death ↑	[91]
3xTg-AD mice HEK-293 cells	RGFP-966	HDAC3i	BDNF expression, H3 and H4 acetylation ↑ Aβ, p-Tau, Tau acetylation ↓	[92]
APP/PS1 mice	VPA	Class I HDACi	Memory deficits ↓ Acetylated H3, Aβ, NF-κB ↓	[99,100]
APP/PS1 mice	BG45	Class I HDACi	H3K9K14/H3 acetylation ↑ Aβ deposition, p-Tau, IBA-1 positive microglia and GFAP-positive astrocytes ↓, synaptophysin ↑, PSD96 ↑, IL-1β, TNF-α ↓	[95]
SH-SY5Y cells	BHB	HDACi	Cell vitality ↑, TrkA ↑, HDAC1/2/3 ↓ Ace-H3K9, AceK4K12 ↓	[101]
Rats	MB3	GCN5 inhibitor	Ace-H3K9, CDK5, Tau phosphorylation ↓ Behavior performance ↑	[103]
Human mixed glial cultures	Vorinostat	Class I and II HDACi	PU.1 ↓	[111]
Tg2576 mice	CM-414	Class I HDACi and PDE5 inhibitor	LTP, GSK3β, Ace-H3K9, spatial memory ↑ p-Tau ↓ Dendritic spine density ↑	[114,121]
Tg2576 mice SH-SY5Y cells	CM-695	HDAC6i	PDE9 ↓, Aβ ↓ Ace-H3K9, memory deficits ↑	[118]
iPSC	Exifone	HDAC1 activator	Histone acetylation and tauopathy ↓	[121]

↓: Decreased; ↑: Increased; Ace: Acetylated; BHB: β-hydroxybutyrate; GCN5: General control nondepressible 5; H4: Histone 4; H3K9: Histone 3 lysine 9; H3K27: Histone 2 lysine 27; H4K12: Histone 4 lysine 12; iPSC: induced pluripotent stem cell; KO: Knock out; LTM: Long-term memory; LTP: Long-term potentiation; MB3: Butyrolactone 3: (GCN5 inhibitor); NaBu: Sodium buturate; ND: Neurodegeneration; p-Tau: Phosphorylated Tau; PBA: 4-phenylbutyrate; PU.1: ETS-family transcription factor; SAHA: Suberoylanilide hydroxamic acid; TrkA: Tyrosine kinase receptor A; TSA: Trichostatin A; TTX: Tetrodotoxin; VPA: Sodium valproate.

A similar multitarget approach was exemplified in a study employing CM-414, a compound inhibiting class 1 HDAC and PDE5. When administered individually, both HDAC and PDE5 inhibitors showed promising outcomes. CM-414 rescued LTP, reduced brain Aβ and p-Tau levels, increased the inactive form of glycogen synthase kinase-3β (GSK3β), restored dendritic spine density and improved learning and memory impairments, partly by promoting the expression of synaptic plasticity genes [122].

Notably, the HAT activity of Tip60 plays a pivotal role in promoting both neuronal and organismal survival in a Drosophila model of AD. This effect is accomplished by upregulating prosurvival factors and simultaneously inhibiting the expression of cell death activators [123]. Furthermore, the overexpression of Tip60 has been associated with enhanced axonal growth in Drosophila circadian neurons. Of particular interest, in conditions of neurodegeneration induced by APP, the overexpression of Tip60 has demonstrated remarkable effects. It rescued axonal outgrowth and transport and ameliorated associated behavioral phenotypes, including improvements in sleep and locomotion [124]. Subsequently, it was revealed that both learning and immediate-recall memory deficits observed under AD-associated, APP-induced neurodegenerative conditions could be mitigated by elevating Tip60 HAT levels, specifically in the Drosophila CNS, particularly in the mushroom body [125]. These findings emphasize the potential therapeutic implications of modulating Tip60 activity in the context of APP-induced neurodegeneration and associated cognitive defects.

In the context of an APP Drosophila model that mimics early human AD, it was observed that Tip60 and HDAC2 primarily bind to the same neuronal genes [126]. Additionally, AD brains display early genome-wide changes, including increased HDAC2 binding and reduced Tip60 binding, leading to transcriptional dysregulation. These findings suggest that Tip60 HAT/HDAC2-mediated disruption of epigenetic neuronal gene expression is an initial causal event in AD [127]. Furthermore, a similar multitarget approach led to the development of compound 31b (CM-695), a selective inhibitor targeting PDE9 and HDAC6 [128]. CM-695 demonstrated significant efficacy in rescuing the AD phenotype in aged Tg2576 mice [129]. In the context of APP/PS1 mice, prolonged administration of CM-414 resulted in reduced Aβ and p-Tau levels, along with the rescue of LTP deficits. Additionally, CM-414 elevated the inactive form of GSK3β, which contributes to microtubule stability via Tau phosphorylation, a process linked to cognition and AD neuropathology [121]. CM-414 also restored dendritic spine density and mitigated spatial memory abnormalities. Overall, CM-414 emerges as a highly promising multitarget therapeutic strategy, aligning with the complex and multifaceted nature of AD neuropathology while minimizing the potential for unintended side effects associated with increased targeting [122]. The induction of early Aβ42 (human) in the Drosophila brain was demonstrated to trigger an imbalance in Tip60 HAT/HDAC2 levels during the initial stages of neurodegeneration, which precedes the accumulation of Aβ plaques. This imbalance persists into the late stages of AD. Elevating Tip60 HAT levels in the Aβ42 fly brain effectively prevents the accumulation of Aβ plaques, neural cell death and cognitive deficits, and extends the lifespan. These beneficial effects are achieved through unique transcriptomic mechanisms that operate during the early and late stages of neurodegeneration [65].

In contrast to HDAC function in histone acetylation in AD, HDACs also acetylate nonhistone proteins and contribute to neuroprotection. For example, HDAC6 reversibly regulates Tau acetylation and suppresses p-Tau in the microtubule-binding region. In addition, HDAC6 becomes coaggregated in focal Tau swellings and human AD neuritic plaques in neurons and the human AD brain. Moreover, Tau transgenic mice lacking HDAC6 show impaired survival via accelerated Tau pathology and cognitive impairments [130]. There are incidences where the activation of certain HDACs protects against neurodegeneration. For instance, exifone, a drug previously shown to be effective in treating cognitive deficits associated with AD, potently activates HDAC1 by directly binding to it. Moreover, it was neuroprotective in a tauopathy-patient induced-pluripotent stem cell-derived neuronal model subject to oxidative stress [131].

In conclusion, the intricate web of histone acetylation changes in AD reflects a complex interplay of genetic, epigenetic and environmental factors that contribute to the disease's progression. Aberrant processing of proteins like Aβ and Tau leads to significant transcriptional modifications mediated by critical factors like ATF-2, CREB, CBP, PCAF and CRTC1. Dysregulation of these factors disrupts critical signaling pathways, contributing to cognitive impairments in AD. Histone acetylation, governed by HDACs, plays a pivotal role in memory formation and maintenance. Notably, HDAC2 emerges as a negative regulator of memory, and strategies to enhance histone acetylation have shown promise in ameliorating memory deficits associated with AD. Additionally, the crosstalk between cGMP and cAMP regulated by PDEs is critical for learning and memory. PDE5 inhibition has demonstrated significant benefits in AD, enhancing memory and reducing Aβ levels. The combination of HDACs and PDE inhibitors, such as CM-414 and CM-695, represents a promising multitarget therapeutic approach for AD, addressing the complex nature of the disease. Moreover, the restoration of epigenetic balance through factors like Tip60 and HDAC6 has shown potential in mitigating AD-related pathology. Overall, these findings highlight the intricate role of histone acetylation and related pathways in AD pathogenesis and suggest various potential targets for therapeutic interventions in the quest to combat this prevalent neurodegenerative disease.

Histone acetylation changes in PD

PD is a neurological disorder characterized by hallmark features including bradykinesia, rest tremor and rigidity [132,133]. Aging, environmental conditions and living standards influence the pathogenesis and progression of PD. Current pharmacotherapy primarily relies on symptomatic approaches, such as dopamine (DA) replacement or modulation. Additionally, nonmotor symptoms often precede motor manifestations, encompassing autonomic and olfactory dysfunction, sleep disturbances, depression and anxiety. The core motor dysfunction in PD stems mainly from the loss of DA-containing neurons in the substantia nigra pars compacta (SNc), a critical brain region regulating movement [134–136]. At clinical presentation, it is estimated that over 60% of SNc DA neurons have already degenerated, with an 80% reduction in DA content in the striatum [134,135,137]. While genetics play a role, they are less pivotal in PD than in many other diseases. Genes like SNCA, LRRK2, PARKIN, PINK1 and GBA1 have been linked to PD [138–142]. However, they account for only approximately 5% of cases, often those occurring before age 60 [143]. Twin studies have further underscored the limited role of genetics as the primary cause [144,145]. In contrast to primary causative genes, PD involves numerous risk genes, with around 90 already identified, which interact with environmental factors to influence disease expression [143,146–149]. Since relatively few PD cases are primarily genetic, environmental factors are pivotal contributors [143].

Due to an aging population and increasing industrialization linked to environmental risks, the prevalence of PD is projected to rise steadily, reaching approximately 13 million cases by 2040 [150]. The challenge in early PD diagnosis lies in the late onset of motor symptoms after substantial dopaminergic neuron loss and the absence of reliable biomarkers [151]. While the complete pathogenesis of PD remains elusive, certain factors, including the loss of dopaminergic neurons [134,135,137], α-synuclein (α-syn) aggregation [152], metal ion accumulation [153] and oxidative stress [154], are known to play pivotal roles [155]. Moreover, like in other NDs, transcriptional dysregulation is a common feature in the progression of PD [156]. Therefore, PD-related causative and susceptibility genes are subject to epigenetic mechanisms, including DNA methylation, histone post-translational modification and regulation by ncRNAs. Nonetheless, the precise influence of aberrant epigenetic changes on gene expression and PD pathology remains unclear. Histone modification, a prominent epigenetic alteration, can be influenced by environmental factors such as exposure to pesticides and industrial agents [157]. In this context, the following section provides an overview of studies concerning histone acetylation changes in PD.

While our comprehension of epigenetic mechanisms in PD is continuously evolving, compelling evidence points to the involvement of mutated α-syn, a pivotal component of Lewy bodies, in the pathogenesis of PD. Early research has shown that mutated α-syn can impede H3 acetylation mediated by CBP, P300 and PCAF in cultured cells, ultimately contributing to cell death [158]. These findings strongly suggest that augmenting histone acetylation could mitigate α-syn-induced neurotoxicity. Notably, studies of NaBu and vorinostat have demonstrated their ability to prevent α-syn-induced apoptotic cell death in vitro and rescue dopaminergic neuron degeneration in α-syn-transgenic flies [158]. Additionally, mutant α-syn exhibits a heightened affinity for nuclear targeting, underscoring that the neurotoxicity associated with mutant α-syn is partially mediated by histone hypoacetylation. Moreover, in primary DA cell cultures exposed to the neurotoxin 6-hydroxydopamine and in a mouse model of PD induced by MPTP [159], the use of HDACi exhibited a neuroprotective effect [160,161]. In addition, these treatments have been shown to induce GDNF expression in midbrain astrocytes. Notably, GDNF gene delivery has been considered a potential therapy for PD [162]. These findings suggest that developing specific HDACi to robustly enhance endogenous GDNF may offer a drug target for PD. However, in other studies, treatment with pan-HDACi exacerbated MPP⁺-induced neurotoxicity in SH-SY5Y cells, whereas HAT activation promoted their survival [163,164], consistent with their function in the development and survival of DA neurons [165]. In a separate investigation, the inhibition of SIRT2 through pharmacological means proved effective in rescuing neuronal α-syn (A53T) toxicity both in vitro and in a Drosophila model of PD [166]. Intriguingly, pharmacological SIRT2 inhibition also influenced α-syn aggregation. Furthermore, in vitro studies indicated that SIRT2 inhibition led to the accumulation of larger α-syn aggregates, which appeared to have a protective effect. In comparison, smaller aggregates were associated with increased toxicity [166]. These early findings suggested that, alongside traditional HDACs, targeting SIRT2 may hold therapeutic promise in PD. However, which of the HDACs should be targeted for optimal therapeutic effect is unclear.

Hyperacetylation of H3 or H4 represents key epigenetic changes in dopaminergic neuron dysfunction. For example, a time-dependent increase in H3 or H4 acetylation in primary neuronal cultures was found upon exposure to dieldrin [167] or paraquat [168,169], environmental toxins implicated in the pathogenesis of PD. These changes were associated with proteasomal dysfunction and CBP accumulation. Furthermore, HAT inhibitors such as anacardic acid significantly inhibited dieldrin-induced dopaminergic neuronal degeneration in cultures, reinforcing the function of H3 and H4 hyperacetylation in neuronal death after toxic exposure. Furthermore, it has been shown that SNP on intron 4 of the α-syn encoding gene (SNCA) prevents EMX2/NKX6.1 recruitment and subsequently repress SNCA gene expression and causes enhanced H3K27 acetylation, otherwise methylated as a consequence of HDAC recruitment [170,171]. A similar observation was reported where H3K27 acetylation in the prefrontal cortex of individuals with PD was significantly increased [172]. In a genome-wide histone acetylation analysis study, H3K27 acetylation, a histone marker of active transcription, was also strongly associated with PD hallmarks, including SNCA, MAPT, APP, PRKN, PARK7, FBOX7 and POLG [172]. Therefore, dysregulation of H3 or H4 acetylation in PD-related neurotoxicity is an important mechanism underlying neuronal loss in PD (Table 3).

Table 3. . Changes in histone acetylation and deacetylation process in Parkinson's disease models.

Model	Drug	Modification	Effects	Refs.
MPTP	–	–	H3 hyperacetylation, H4 deacetylation	[173]
6-OHDA	–	–	SIRT2 ↓, tubulin hyperacetylation	[174]
Levodopa	–	–	H4 deacetylation, dyskinesia	[173]
Dieldrin-dopaminergic neurons	Anacardic acid	HAT inhibitor	Histone deacetylation, DA neuron apoptosis ↓	[168]
DJ-1 (Park 7)-gene knockout rat	Curcumin	HAT inhibitor	DA neuron apoptosis ↓	[175]
6-OHDA in rat	SB	Class I and IIa HDACi	Histone acetylation and Bdnf ↑ Motor deficits ↓	[176]
Rotenone-induced Drosophila	SB	Class I and IIa HDACi	Locomotor deficits ↓, rotenone-mediated DA ↓	[177]
Cell culture and transgenic Drosophila	SB	Class I and IIa HDACi	Syn-associated toxicity ↓	[177]
MPTP in mice	SB	Class I and IIa HDACi	MPTP-induced DA neuron death ↓	[178]
Dopaminergic cells	SB	Class I and IIa HDACi	Histone acetylation ↑, neuroprotection	[179]
Drosophila	SPB	Class I and II HDACi	Neuroprotection	[159]
Cell culture and animal model	SPB	Class I and II HDACi	DJ1 expression ↑, neuroprotection	[180]
MPTP in mice	SPB	Class I and II HDACi	Neuroinflammation ↓, oxidative stress ↓	[181]
Neuron-glia and reconstituted cultures	SAHA	Class I, II and IV HDACi	Cell survival ↑ DA neurons death ↓	[182]
Cell culture and transgenic Drosophila	–	–	H3 acetylation ↓ α-Syn-mediated neurotoxicity ↓	[158]
Cell culture and transgenic Drosophila	–	–	HAT ↓	[158]
Cell culture and transgenic Drosophila	SAHA	Class I, II and IV HDACi	α-Syn-mediated neurotoxicity ↓	[158]
Human SK-N-SH and rat 23.5 cells	SAHA	Class I, II and IV HDACi	MPP+-mediated apoptosis ↓	[183]
SH-SY5Y neuroblastoma cells	SAHA	Class I, II and IV HDACi	α-Syn-mediated neurotoxicity ↓	[177]
Drosophila model	TSA	Class I and II HDACi	α-Syn-mediated neurotoxicity ↓ Early mortality ↓	[176,177]
Neuron-glial cultures	TSA	Class I and II HDACi	GDNF and BDNF ↑ Neuroprotection	[161]
SH-SY5Y neuroblastoma cells	TSA	Class I and II HDACi	TH and Bdnf expression ↑ MPP+-mediated toxicity ↓	[184]
Neuron-glial cultures	VPA	Class I HDACi	Gdnf and Bdnf expression ↑ DA neurons death ↓	[160]
Neuron-glial cultures	VPA	Class I HDACi	Neurotrophic factors ↑, DA neurons death ↓	[182]
Rotenone-induced mice	VPA		H3 acetylation ↑, neurotoxicity ↓	[185]
MPTP in mice	VPA	Class I HDACi	Histone acetylation ↑, neuroprotection ↑	[186]
SH-SY5Y neuroblastoma cells	VPA	Class I HDACi	HSP70 ↑, DA neuron death↓ Neuroprotection ↑	[187,188]
LRRK2 R1441G mutation	VPA	Class I HDACi	Activation of microglia ↓ Motor behavioral deficits ↓	[189]
SH-SY5Y neuroblastoma cells	LMK235	Class IIa HDACi	BMP-Smad signaling ↑ Neurite outgrowth ↑	[190]
6-OHDA in rat	MC1568	Class IIa HDACi	DA neuron death ↓	[191]
Neurons and microglia	AGK2	Class III SIRT2i	DA neuron death ↓ Activation of microglia ↓	[192]
MPTP in mice	AK-7	Class III SIRT2i	Neurochemical defects ↓ Behavioral abnormalities ↓	[193]
6-OHDA in rat	Resveratrol	Class III SIRT1i	Neuroprotection	[194]
MPTP in mice	Resveratrol	Class III SIRT1i	DA depletion ↓, TH protein levels ↑	[195]
SK-N-BE cells	Resveratrol	Class III SIRT1i	Oxidative stress ↓ α-syn (A30P) aggregation ↓	[196,197]
PC12 cells	Resveratrol	Class III SIRT1i	Rotenone-induced PC12 cell apoptosis ↓ MPP+-induced PC12 cell apoptosis ↓	[198,199]
6-OHDA in mice	Honokiol	Class III SIRT3i	Motor impairments ↓	[200]
Cell culture	ϵ-Viniferin	Class III SIRT3i	SIRT3 expression ↑, FOXO3 deacetylation ↑ Oxidative stress ↓, rotenone-induced apoptosis ↓	[201]

↓: Decreased; ↑: Increased; 6-OHDA: 6-Hydroxydopamine; BMPs: Bone morphogenetic proteins; DA: Dopamine; H3: Histone 3; HDACi: Histone deacetylase inhibitor; MPP⁺: 1-methyl-4-phenyl-pyridinium ion; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SAHA: Suberoylanilide hydroxamic acid; SB: Sodium butyrate; SPB: Sodium phenylbutyrate; TH: Tyrosine hydroxylase; TSA: Trichostatin A.

Based on initial findings, several researchers have used available HDACi based on their specificity to specific classes of HDACs as neuroprotective agents in many PD models. For instance, pharmacological inhibition of class I HDACs, namely HDAC1 and HDAC2, has been reported to attenuate MPP⁺-induced toxicity in SH-SY5Y cells and MPTP-induced death of DA neurons in mice in vivo [163]. Additional studies have shown that inhibition of HDAC6 (tubastatin A) and HDAC1 (MS275) rescued MPP⁺-induced motor impairment in a zebrafish model of PD [202]. Enhanced histone acetylation was found in midbrain DA neurons of patients with PD compared with matched control individuals [203]. Further investigation in MPP⁺-treated cells, MPTP-treated mice brains and the midbrain tissues of human patients with PD resulted in reduced levels of HDACs. Consistent with these observations, siRNA-mediated inhibition of HDAC1 and HDAC2 potentiated MPP⁺-induced cell death. These findings indicated that the PD condition results in the degradation of HDACs and promotes histone acetylation [203]. In the same study, inhibition of HAT was neuroprotective [203]. The function of HDAC3 in PD has been demonstrated in a study indicating that PTEN-induced PINK1 mutations are associated with autosomal recessive PD, where enhanced HDAC3 was associated with reduced neuronal death via apoptosis [204]. Class II HDACs have been shown to function in PD, as suggested by studies in cultured DA neurons from WT and mutant α-synu or A53T mutant α-syn transgenic mice or control transgenic mice exposed to MPP⁺. In these studies, increased DA neuronal death was associated with nuclear accumulation of HDAC4 in vitro and in vivo in α-synu transgenic mice treated with MPTP [205]. A similar enhanced HDAC4 was found in a study of iPSC-derived DA neurons from a patient with PD, which revealed that HDAC4 acted as a repressor of a set of 60 genes that were significantly upregulated or downregulated compared with age-matched controls [206]. Another class II HDAC, HDAC5, was upregulated following methamphetamine-induced neuronal death and resulted in upregulation in 80 distinct samples from 40 different brain regions of adult mice [207]. In addition, inhibition of HDAC5 and HDAC9 is neuroprotective in both MPP⁺ and α-syn cell models of PD [208,209]. HDAC4/5 inhibition with LMK235 has demonstrated a remarkable capacity to enhance histone acetylation while promoting neurite outgrowth in human SH-SY5Y cells and DA neurons in primary cultures derived from embryonic day 14 rat ventral mesencephalon. Importantly, when exposed to MPP⁺, LMK235 treatment exhibited robust neuroprotective effects in SH-SY5Y cells and cultured DA neurons. Furthermore, the neuroprotective attributes of LMK235 extended to the context of axonal degeneration triggered by the overexpression of WT or A53T mutant α-syn [190]. This protective effect was evident in SH-SY5Y cells and primary cultures of DA neurons, underlining the potential therapeutic utility of targeting HDAC4/5 by a specific inhibitor (LMK235) against α-syn-associated neuropathological processes. These studies suggest that upregulation and nuclear accumulation of class IIa HDACs may be detrimental, and inhibition with specific inhibitors appears neuroprotective for DA neurons. In contrast to class IIa HDACs, class IIb HDAC (HDAC6) overexpression was shown to rescue misfolded protein accumulation following autophagy activation in a Drosophila transgenic model of PD [210].

In conclusion, PD is a complex neurological disorder influenced by various factors such as aging, environmental conditions and genetics. The prevalence of PD is expected to increase due to an aging population and environmental risks, making early diagnosis challenging. PD is characterized by the loss of DA-containing neurons in the brain's substantia nigra pars compacta, leading to motor symptoms like bradykinesia and tremors. Nonmotor symptoms often precede motor manifestations. Although genetics sometimes play a role, epigenetic mechanisms are increasingly recognized as important contributors to PD pathogenesis. Studies suggest that epigenetic modifications, including histone acetylation changes, are involved in PD. Mutated α-syn, a key component of Lewy bodies in PD, can impact histone acetylation, potentially contributing to neurotoxicity. Some HDACi have shown promise in protecting dopaminergic neurons, but the specific HDACs to target for optimal therapeutic effects remain uncertain. Hyperacetylation of histones H3 and H4 is associated with dopaminergic neuron dysfunction and neuronal death, mainly when triggered by environmental toxins. Dysregulation of histone acetylation has been observed in PD-related neurotoxicity. Furthermore, several researchers have explored the potential of HDACi as neuroprotective agents in PD models with promising results. Class I HDACs, HDAC1 and HDAC2 have shown neuroprotective effects, as have specific inhibitors targeting class IIa HDACs, such as HDAC4 and HDAC5. HDAC6, a class IIb HDAC, has demonstrated potential in mitigating misfolded protein accumulation. Therefore, histone acetylation changes play a significant role in PD pathogenesis. Targeting specific HDACs or promoting histone acetylation could offer therapeutic strategies for this complex and challenging disease. Further research is needed to understand the precise impact of epigenetic changes on PD pathology and develop effective treatments.

Histone acetylation changes in HD

HD is a progressive ND characterized by late-onset symptoms and is attributed to a trinucleotide CAG repeat in exon 1 of the Huntingtin (Htt) gene [211–213], leading to motor, cognitive and psychiatric manifestations [214,215]. Prominent features associated with the earliest stages of HD encompass modifications in chromatin structure and the perturbation of neuronal gene transcription. Investigations spanning recent decades, employing patient samples and diverse animal models, have spotlighted histone modifications (acetylation, methylation, ubiquitylation and phosphorylation; see review [216]), along with DNA modifications, as pivotal epigenetic alterations orchestrating gene expression in HD. Approaches rooted in pharmacology, aimed at rectifying specific epigenetic shifts, have revealed potential avenues for HD treatment (see review [217]). This article captures the latest advances in histone acetylation-mediated epigenetics, offering promising insights for prospective HD interventions.

The mutant Huntingtin protein (mHTT) has been shown to induce mitochondrial dysfunction, changes in energy metabolism, oxidative stress and abnormal aggregation between HTT and other proteins [218]. These alterations can result from the dysregulation of transcriptional machinery and an altered gene expression pattern or visa versa. Several critical proteins from the transcriptional machinery have been shown to aggregate in the presence of mHTT and were altered in their function. These proteins include CBP, SP1 and TBP, among others, which results in defective gene transcription [219]. Genome-wide expression studies have unveiled novel targets and propelled our understanding of the molecular underpinnings of HD. Profiling transcription in human HD brains and employing in vivo and in vitro disease models have illuminated sweeping alterations in the expression of both coding and ncRNAs [220]. A spectrum of mechanisms, encompassing the sequestration and soluble interaction-mediated inhibition of positive transcriptional regulators, alongside the loss of restraint on negative transcriptional regulators, has been posited to elucidate how the mutant HTT precipitates transcriptional dysregulation [221].

Histone acetylation, a process that promotes gene transcription, is reduced in many HD models [222,223]. However, enhanced histone acetylation has been observed at specific gene loci [224]. Different researchers have demonstrated altered histone acetylation in various HD models and neuronal populations from patients [225]. Notably, significant reductions in acetylated H2A, H2B, H3 and H4 proteins have been observed in the caudate nucleus and Purkinje cells of the cerebellum in patients with HD compared with matched controls [226]. Although acetylated histone levels were not altered, a significant reduction in H3 acetylation was found at the promoters of downregulated genes in younger R6/2 mice compared with control littermates. Administration of HDACi rescued the downregulated genes [227]. Whole-genome analysis in R6/2 HD model mice identified an association between histone modifications and transcriptional abnormalities in the striatum and revealed reduced binding sites occupied by acetylated histone H3. Acetylated H3K9 and H3K14 were localized at genes strongly expressed in WT and HD mice models. However, moderately increased acetylated H3 binding was found at select gene loci [224].

As previously discussed, with its HAT activity, CBP regulates various neural functions, including stress response [228], synaptic plasticity and synaptic communication [229]. Abnormal transcriptional regulation plays a pivotal role in HD pathogenesis. CBP sequestration disrupts CRE-mediated transcription [219,230], as observed in HD transgenic model R6/2 [231]. Consistent with these findings, other studies have shown that reducing CBP aggregation can mitigate HD pathology in R6/2 mice models [232]. In patients with HD and HD model mice-derived cells, the depletion of CBP from its usual nuclear location has been associated with the inclusion bodies produced by mHTT protein aggregation and other proteins, resulting in reduced soluble CBP. Recruitment of CBP to mHTT causes aggregation, followed by enhanced degradation via the ubiquitin-proteasome system. These events reduce CBP activity and dysregulation of the CBP target gene's transcription [233]. Furthermore, mHTT physically interacts with CBP, resulting in the loss of CBP-mediated gene expression [192], followed by neuronal loss [230,231,234]. Unlike CBP, P300 does not undergo sequestration in mHTT-induced inclusions or promote degradation through the ubiquitin–proteasome system [230]. Additionally, overexpression of P300 cannot rescue cells from mHTT toxicity [235]. In a cell-free system, the protein encoded by HTT exon 1 can inhibit the HAT activity of P300, P/CAF and CBP. For example, the expression of HTT exon 1 in cultured cells reduced acetylated H3 and H4 levels, which could be rescued by exposure to HDACi [236]. In the PC12 cell line, the expression of an expanded polyQ (148Q) N-terminal truncation of the HTT gene reduced HAT activity and global histone acetylation compared with normal HTT expression [237]. These observations strongly indicate that CBP's HAT activity plays an undeniable role in the progression of HD through changes in the transcriptional network and likely contributes to shaping the regulatory landscape associated with the disease.

Extensive investigations have been designed to elucidate the specific role of individual HDACs in HD pathogenesis. Various genetic strategies have been employed to identify HDAC targets with therapeutic implications for HD. For example, in Drosophila models, alleviating transcriptional repression either by genetically reducing Sin3A corepressor activity or administering HDACi rescued lethality and photoreceptor neurodegeneration [236]. Furthermore, when SAHA was administered in drinking water with 2-hydroxypropyl-β-cyclodextrin, it restored reduced histone acetylation, striatal neuronal loss and motor impairment in the R6/2 mouse model [238]. Prolonged SAHA treatment in R6/2 mice reduced protein aggregate load, restored Bdnf levels and reduced HDAC2, HDAC4, HDAC7 and HDAC11 [239]. HD disease progression has been associated with increased HDAC1 levels and decreased HDAC4, 5 and 6 levels in cortices and striatal tissues of HD R6/2 mice [240]. However, no significant changes in HDAC1 levels were found in human HD brains [240]. Mutant HTT protein accelerates the nuclear import of HDAC5 (class II) but not HDAC1 or HDAC8 (class I) [241]. Some HDACi (e.g., TSA or NaBu) were more efficient in regulating calcium levels and improving the ability of neurons to cope with excitotoxic insults in striatal neurons from HD mice models [242]. Specific HDAC1 and HDAC3 inhibitors (4b and 136) were the most effective in rescuing the expression of genes relevant to HD in R6/2 mice models [243]. Similarly, specific HDAC1 and HDAC3 (RGFP109) inhibition alleviated motor phenotypic deficits and transcriptional dysregulation in R6/1 mice models [244]. While HDAC1 and HDAC2 were localized to the nucleus in R6/2 mice compared with WT, localization of other HDACs such as HDAC2, HDAC4 and HDAC7 were not affected in this animal model [243]. These observations strongly indicate that different HDACs play a definite role in the regulation of the transcriptional network and likely contribute to the progression of the disease.

Targeted HDACi displayed a neuroprotective function in HD pathogenesis (Table 4). For example, 4b, an HDACi administered orally after the onset of motor deficits, significantly rescued various aspects of R6/2(300Q) transgenic mice, including gene expression defects, motor performance, appearance and body weight [245]. Additionally, it ameliorated body weight loss, impaired motor function and cognitive deficits induced by HTT in N171–82Q transgenic mice. This effect was achieved by modulating the ubiquitin-proteasomal and autophagy pathways [246]. In addition, HDAC4 was found to associate with HTT protein in a polyglutamine-length-dependent manner and colocalized with cytoplasmic inclusions. Knocking down HDAC4 delayed cytoplasmic aggregate formation without affecting nuclear HTT aggregation. This led to the rescue of Bdnf levels and improved neuronal and corticostriatal synaptic function, resulting in enhanced motor coordination, neurological phenotypes and increased lifespan [247]. Surprisingly, HDAC4 KD did not influence global transcriptional dysfunction [247]. Further, HDAC4 is enriched with functions related to synaptic plasticity and vesicle trafficking, as evaluated by integrating proteome and transcriptome data sets from the striatal tissues of Q140 HD mouse models [248]. HDAC4 degradation in cultured mouse primary cortical neurons prepared from Q175 knock-in mice resulted in delayed aggregation of mHTT, along with amelioration of neurological phenotypes and extended lifespan [248]. These findings further reinforce the relevance of HDAC4 in HD [249]. In contrast, HDAC3 directly binds to HTT and contributes to neurotoxicity in an HD mouse model. HDAC3 preferentially binds to nuclear HTT over cytoplasmic HTT, and inhibiting HDAC3 leads to an elevation in the total amount of HTT aggregates, particularly nuclear aggregates. Both cytoplasmic and nuclear HTT aggregates were found to suppress endogenous HDAC3 activity, which precedes reduced nuclear proteasome activity [250]. These findings suggest that HTT aggregates impair nuclear proteasome activity by inhibiting specific HDACs, including HDAC3. A broad HDACi, panobinostat, rescued neuronal shrinkage in R6/2 mice and significantly prevented the behavioral and neuropathological phenotypes in CAG140 knock-in mice [251]. This drug, administered as a presymptomatic intervention, effectively improved behavioral changes and markers of dopaminergic neurotransmission in vitro and in vivo [252].

Table 4. . Changes in histone acetylation and deacetylation process in Huntington's disease models.

Model	Drug	Modification	Effects	Ref.
HD cell culture models, HD transgenic mice and human HD postmortem brain	–	–	CBP-activated gene transcription ↓	[230]
Httex1p cell-free in vitro and Httex1p-QP in PC12 cell lines	–	–	p300, P/CAF and CBP-HAT activity ↓ Acetylated H3 and H4 levels ↓	[236]
Httex1p-QP in PC12 cells	SB	Class I and IIa HDACi	Acetylated H3 and H4 levels ↑	[236]
	TSA	Class I and II HDACi
	SAHA	Class I, II and IV HDACi
HT22 hippocampal cell line	–	–	CBP ubiquitylation and degradation ↑	[233]
N63–148Q-PC12 cells	–	–	Histone acetylation ↓, HAT activity ↓	[237]
R6/2 transgenic mice	SB	Class I and IIa HDACi	Survival ↑, motor performance ↑ Neuropathological sequelae ↓	[222]
N171–82Q transgenic mice	SPB	Class I and II HDACi	Histone acetylation ↓, striatal neuron death ↓, neuroprotection	[159]
Httex1p-Q74 in PC12 cells	–	–	CBP and CBP-HAT activity ↓	[235]
Mouse (109Q/109Q) primary striatal and cortical cells	TSA	Class I and II HDACi	Bdnf ↑, α-tubulin acetylation ↑	[253]
R6/2 mice, ST14a and STHdh cells	–	–	H3 acetylation at downregulated (Drd2, penk1, Actb) genes ↓	[227]
R6/2 mice, ST14a and STHdh cells	SPB	Class I and II HDACi	H3 acetylation at downregulated (Drd2, penk1, Actb) genes ↑	[227]
Human blood samples from patients with HD	–	–	H2AFY mRNA ↑	[254]
R6/2 transgenic mice	SPB	Class I and II HDACi	H2AFY mRNA ↓ HD disease amelioration changes ↑	[254]
R6/2 transgenic mice	SAHA	Class I, II and IV HDACi	HDAC4 levels ↓, HDAC2 levels ↓ Bdnf mRNA ↑	[239]
R6/2 transgenic and 140 CAG mice	AK-7	Class III SIRT2i	Aggregated mtHTT ↓, brain atrophy ↓ Motor function ↑ Neuropathological sequelae ↓	[255]
R6/2 transgenic mice	–	–	H3 acetylation at specific genes ↓	[224]
R6/2 transgenic mice	SPB	Class I and II HDACi	H3 acetylation at Homer1 and Cacna2d3 genes ↑	[224]
Postmortem brain tissues from patients with HD	–	–	Acetylated H2A and H3 ↓	[226]
N171–82Q transgenic mice	RGFP966	Class I HDACi	Motor function ↑ Ccl17 ↑; Mif ↓; Il13 ↓; GFAP+ cells ↓	[256]
Postmortem HD cases; OVT73 transgenic sheep and Htt-97Q cells	–	–	Acetylated H4 ↑	[257]
Htt-128Q Drosophila	–	–	HDAC2 (Rpd3) mRNA ↑ Tip60 mRNA ↑	[258]
R6/2 transgenic mice	TFMO, 12	Class IIa HDACi	Acetylated H4K12 ↑	[259]
HD Drosophila	–	–	Gcn5-dependent acetylation of H3.3K14 ↑	[260]
R6/1 transgenic mice	–	–	Acetylated H3K27 ↓, acetylated H3K9 ↓	[261]
R6/2 transgenic mice			CBP ↓; acetylated H3K27 ↓; Bcl6 and Egr1 genes ↓	[262]
YAC128 transgenic mice	CKD-504	HDAC6i	mHTT ↓, tubulin acetylation ↑ Microtubule stabilization ↑ Axonal transport ↑, behavioral deficits ↓	[263]

↓: Decreased; ↑: Increased; 6-OHDA: 6-Hydroxydopamine; BMP: Bone morphogenetic protein; CC: Cingulate cortex; CN: Caudate nucleus; DA: Dopamine; Gcn5: General control nondepressible 5; H2AFY: H2A histone family member Y; H3: Histone 3; HDACi: Histone deacetylase inhibitor; HD: Huntington's disease; IR: Immunoreactivity; MPP⁺: 1-methyl-4-phenyl-pyridinium ion; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PC: Purkinje cells; SAHA: Suberoylanilide hydroxamic acid; SB: Sodium butyrate; SPB: Sodium phenylbutyrate; TH: Tyrosine hydroxylase: TSA: Trichostatin A.

Impairment in α-tubulin acetylation was observed in HD brains [253]. Microtubule acetylation plays a role in recruiting molecular motors like dynein and kinesin-1 to microtubules, facilitating vesicle flux and BDNF release. These processes were defective in the HD brain. HDACi such as tricostatin A promote acetylation at lysine 40 of alpha-tubulin, increasing vesicle flux and subsequent BDNF release [253]. However, genetic deletion of HDAC6, another tubulin deacetylase, increased tubulin acetylation throughout the brain but did not affect BDNF levels or rescue pathological HD-related phenotypes in R6/2 mice [264]. A study involving the genetic KD of HDAC7 in R6/2 HD mice yielded inconclusive results, as it failed to elicit discernible improvements in various physiological, behavioral and transcriptional phenotypes characteristic of the R6/2 HD mouse model [265]. Nonetheless, the noncatalytic domain of HDAC7 has been shown to protect neurons from apoptosis through its direct association with the c-jun gene promoter and c-jun expression [266]. These findings emphasize that α-tubulin acetylation mediated transport deficit in HD pathology and HDACi as a therapeutic interest in this pathology.

Sirtuins, a family of NAD⁺-dependent HDACs, regulate various cellular activities, including deacetylation. SIRT1, in particular, plays a significant role in HD. It deacetylates histones (H1K26, H3K9, H3K56 and H4K16) to regulate chromatin remodeling and gene transcription. SIRT1 maintains BDNF levels [267] by transactivating a BDNF promoter region coregulated by the CREB transcription factor. It also interacts with TORC1, an enhancer of CREB function, contributing to SIRT1-mediated BDNF transcription [268]. SIRT1 activity is downregulated in the brains of HD mouse models (R6/2 and HdhQ150) [269]. Genetically enhancing SIRT1 expression provides neuroprotection in transgenic mouse models of HD [267]. In contrast, SIRT2 inhibition reduces HTT toxicity [270]. A randomized, double-blind, placebo-controlled multicenter exploratory clinical trial with selisistat (a selective inhibitor of SIRT1/SIRT2) showed safety and tolerability for patients with HD [271] and is currently in phase III clinical trials for treating HD [272]. These observations highlight the intricate and nuanced relationship between specific HDACs, tubulin acetylation and sirtuins in the context of HD pathology. Further research in these areas holds promise for therapeutic strategies to address this devastating disease.

In conclusion, HD is a complex ND characterized by progressive motor, cognitive and psychiatric symptoms driven by a trinucleotide CAG repeat expansion in the HTT gene. Emerging research has shed light on the pivotal role of epigenetic modifications, particularly histone acetylation, and the involvement of HATs and HDACs in the pathogenesis of HD. Studies have demonstrated altered histone acetylation patterns in various HD models and patient samples, offering insights into the intricate mechanisms underlying gene dysregulation in the disease. Histone acetylation changes have been associated with specific gene loci and neuronal populations affected in HD. Furthermore, the dysregulation of transcriptional machinery, particularly the sequestration of critical transcriptional regulators like CBP, contributes to the transcriptional abnormalities observed in HD. The intricate relationship between HDACs and HD pathology is becoming increasingly apparent. Selective targeting of specific HDACs, such as HDAC1 and HDAC3, has shown promise in rescuing gene expression changes and alleviating HD-related phenotypes in various mouse models. Additionally, the role of sirtuins, a class of NAD⁺-dependent HDACs, in regulating chromatin remodeling and gene transcription has garnered attention, with SIRT1 and SIRT2 emerging as potential therapeutic targets. While progress has been made in understanding the epigenetic landscape of HD and the potential of HDACi in treatment, further research is needed to unravel the intricacies of epigenetic modifications and their specific roles in HD pathogenesis. The ongoing exploration of epigenetic mechanisms promises to open new avenues for therapeutic interventions in HD, offering hope for improved treatments and, ultimately, a better quality of life for affected individuals.

Conclusion

Three NDs, AD, PD and HD, share a common thread of intricate histone acetylation changes and epigenetic dysregulation in their pathogenesis. In AD, histone acetylation alterations reflect a complex interplay of genetic, epigenetic and environmental factors contributing to disease progression. Dysregulation of key factors like ATF-2, CREB, CBP, PCAF and CRTC1 disrupts critical signaling pathways, leading to cognitive impairments. Strategies targeting histone acetylation and the crosstalk between the cGMP and cAMP pathways offer a promising multitarget therapeutic approach for AD. In PD, a complex interplay of aging, environmental factors and genetics contributes to this ND. Histone acetylation changes, impacted by α-syn mutations, can lead to neurotoxicity. Specific HDACi and histone acetylation modulation hold promise as neuroprotective strategies in PD, with class I HDACs and class IIa HDACs showing potential. A trinucleotide CAG repeat expansion in the HTT gene in HD drives progressive motor, cognitive and psychiatric symptoms. Histone acetylation modification is pivotal in HD pathogenesis. Selective targeting of HDACs, particularly HDAC1 and HDAC3, offers hope for rescuing gene expression changes and alleviating HD-related phenotypes. In all three disorders, understanding the intricate landscape of histone acetylation changes and the roles of specific HDACs and epigenetic factors is crucial for developing effective therapeutic interventions. Further research is needed to uncover precise mechanisms and optimize treatments for these challenging neurodegenerative diseases.

Future perspective

In the future, the exploration of genomics and epigenetics is poised to unlock even deeper insights into the intricate mechanisms of DNA/RNA methylation and histone modifications regulating gene expression in response to stress, aging and disease. The growing interest in deciphering the epigenetic underpinnings of neuronal plasticity is expected to reshape our understanding of brain rewiring throughout various life stages, encompassing development, aging and the complex landscape of NDs. A noteworthy focus will be addressing histone acetylation dysregulation, a shared characteristic in diverse brain disorders. This anomaly is anticipated to take center stage as a therapeutic target, with HATs and HDACs emerging as promising candidates for intervention in the treatment of NDs such as AD, PD and HD. The future holds exciting prospects for novel therapies that target the intricate balance of histone acetylation, offering hope for mitigating the progression of devastating brain disorders. Moreover, as we delve deeper into the genetic–environmental interplay through advanced models and studies, we anticipate uncovering molecular changes that correlate with behavioral insights. This holistic approach may provide early intervention possibilities, enabling targeted strategies to modulate the epigenome in at-risk individuals. Integrating genetic and environmental factors promises to yield a more nuanced understanding of the pathophysiological processes underlying NDs, paving the way for innovative interventions and personalized therapeutic approaches.

Executive summary.

• Neurodegenerative disorders pose a significant global burden, causing disability and mortality on a large scale.

• These disorders involve the progressive degeneration of neurons, resulting in the loss of neuronal connections and function, ultimately leading to impaired brain activity.

• Current treatments for degenerative brain diseases primarily focus on symptom management, as specific mechanisms and targets for neurodegenerative disorders remain elusive.

Epigenetics changes in neurodegenerative disorders

• Recent advancements in epigenetics suggest that targeting epigenetic modifications holds promise for pharmaceutical interventions in neurodegenerative disorders.

• Emerging epigenetic approaches highlight the pivotal role of histone acetylation processes, regulated by histone acetyltransferases and histone deacetylases (HDACs), in various neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

Conclusion

• Strategies targeting histone acetylation and the crosstalk between cGMP and cAMP pathways present a promising multitarget therapeutic approach for Alzheimer's disease.

• Specific HDAC inhibitors and modulation of histone acetylation show promise as neuroprotective strategies in Parkinson's disease, with class I HDACs and class IIa HDACs demonstrating significant potential.

• Selective targeting of HDACs, especially HDAC1 and HDAC3, holds promise for rescuing gene expression changes and alleviating Huntington's disease-related phenotypes.