The Essential Role of Epigenetic Modifications in Neurodegenerative Diseases with Dyskinesia

Abstract

Epigenetics play an essential role in the occurrence and improvement of many diseases. Evidence shows that epigenetic modifications are crucial to the regulation of gene expression. DNA methylation is closely linked to embryonic development in mammalian. In recent years, epigenetic drugs have shown unexpected therapeutic effects on neurological diseases, leading to the study of the epigenetic mechanism in neurodegenerative diseases. Unlike genetics, epigenetics modify the genome without changing the DNA sequence. Research shows that epigenetics is involved in all aspects of neurodegenerative diseases. The study of epigenetic will provide valuable insights into the molecular mechanism of neurodegenerative diseases, which may lead to new treatments and diagnoses. This article reviews the role of epigenetic modifications neurodegenerative diseases with dyskinesia, and discusses the therapeutic potential of epigenetic drugs in neurodegenerative diseases.

Introduction

In general, the patterns and phenotypes of epigenetic modifications still exist, although there is no change in the primary DNA sequence. Epigenetic modifications have, therefore, been described as a mechanism to control gene expression. Recently, researchers have been drawn to the potential mechanism of epigenetic modifications and its crucial role in neurodegenerative diseases. DNA methylation and histone modifications have been reported as drivers of epigenetic mechanisms. Epigenetic modification can participate in many molecular biological processes, including gene expression, protein–protein interactions, cell differentiation, and embryonic development (Berson et al. 2018; Hwang et al. 2017).

In mammals, epigenetic modifications are required for various gene expressions during development (Fraga et al. 2005; Kaminsky et al. 2009; Rideout et al. 2001). Researchers have revealed that many diseases are caused by the wrong pattern of epigenetic modifications at the wrong time or place (Esteller 2002). In adulthood, epigenetic modifications can still regulate brain function. The role of epigenetic modifications is mainly reflected in genetic inheritance and information transmission of neurons. Failure of these processes may disrupt cognitive and motor functions and lead to neurodegenerative diseases (Hwang et al. 2017). Increasing research has shown that epigenetic modifications are proven associated with the plasticity, homeostasis, the stress response of central nervous system, and several motor disorders. This paper introduces the role of epigenetic modifications in a series of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and so on.

Epigenetic Modifications

The Main Regulatory Mechanism of Epigenetics

Epigenetic modifications can regulate complicated biological functions without altering the nuclear sequence of a gene. This is a mechanism of gene transcriptional regulation, and studies have shown that this process is usually reversible. Epigenetic modifications mainly include DNA methylation (Iyer et al. 2011), histone modifications (Hassig and Schreiber 1997), chromatin remodeling, N6-methyladenosine (m⁶A) modification, and regulation of related genes by non-coding RNA (Suh and Blelloch 2011). After birth, the central nervous system (CNS) is affected by the external environment and drugs, resulting in erroneous epigenetic modifications and changes in gene expression, which inhibits neuronal functions (Arney and Fisher 2004; Dias and Ressler 2014) (Fig. 1).

Fig. 1.

The schematic diagram of epigenetics. Several types of epigenetic mechanisms have been discovered, including DNA methylation, histone modifications, chromatin remodeling, m⁶A modification, and the regulation of non-coding RNA. Epigenetic modifications can regulate various biological functions, such as cell apoptosis, oxidative stress, autophagy, neuronal plasticity, cognitive, and motor function

DNA Methylation

In mammals, 5-methylcytosine (5mC) is the basic form of DNA modification, which is associated with the occurrence and development of diseases (Li and Zhang 2014; Smith and Meissner 2013). DNA methyltransferase (DNMT), which includes DNMT1, DNMT3A, and 3B, can transfer the methyl of S-adenosyl methionine (SAM) to cytosine (Bestor 2000; Cheng 1995; Pradhan et al. 1999; Szyf 2005). DNA methylation is one of the complex mechanism in gene regulation. Cytosine-phosphate-guanine (CpG) dinucleotide, as an epigenetic regulator, is involved in the regulation of gene silence. CpG island contains with a 200 bp region (Bird 2002; Brenner and Fuks 2006), in which the GC content is more than 50%, and the expected CpG ratio is greater than 0.5 (Gardiner-Garden and Frommer 1987). Mammalian genomes contain millions of 5-methylcytosine residues, and 40% of the gene promoters contain CpG islands (Bestor 2000). Most CpG sites are modified by 5mC1, which can mediate the regulation of transcription in the mammalian genome (Bird 2002; Brenner and Fuks 2006). Generally, 5mC is chemically stable, and a barrier for methyl removal is formed through stable carbon–carbon bonds. Based on the stable chemical structure, 5mC can nonetheless be dynamically reversed to an unmodified state in numerous ways. The process of active DNA demethylation mainly includes repeated oxidation of 5mC, excision of 5-carboxylcytosine (5caC) and 5-formylcytosine.

Dynamic DNA demethylation can be regulated at different levels, such as transcription, post-transcription, and post-translation. In addition, genomic-specific demethylation regulators can also regulate this dynamic process (Shen et al. 2014). Researchers found the process of demethylation other than TET protein (Bochtler et al. 2017; Wu and Zhang 2010, 2014). The first mechanism is similar to the process of converting thymine to uracil. Decarboxylase can directly remove the 5-carboxyl group of 5caC (Smiley et al. 2005). The second mechanism is the direct removal of 5-hydroxymethyl from 5-hydroxymethyl cytosine (5hmC) to form unmodified cytosine. In vitro studies have shown that DNA methyltransferases can restore 5hmC to unmodified state without methyl donor (Chen et al., 2012; Liutkeviciute et al., 2009). The third mechanism is that DNMT increases the conversion of 5mC to 5hmC, which promotes the possibility of replication-dependent DNA demethylation (Hashimoto et al. 2012; Valinluck and Sowers 2007).

m⁶A Modification

m⁶A modification is a ubiquitous modification in all eukaryotic mRNA, and it is a dynamic and reversible modification (Wei et al. 1975). It represents over 80% of RNA methylation and exists in various species (Adams and Cory 1975; Bodi et al. 2010; Canaani et al. 1979; Chen-Kiang et al. 1979; Levis and Penman 1978; Narayan et al. 1987; Zhong et al. 2008). m⁶A regulates many aspects of RNA, including RNA splicing, output, translation, and decay (Roundtree et al. 2017a, b; Roundtree et al. 2017a, b; Wang et al. 2014a, b; Wang et al. 2015; Xiao et al. 2016). m⁶A methyltransferase includes Wilms tumor-associated protein, KIAA1429, RNA binding motif protein 15/15B, methyltransferase-like 3/14/16 (METTL3/14/16), CBL proto-oncogene-like 1, virus-like m⁶A methyltransferase related, E3 ubiquitin-protein ligase, and zinc finger CCCH-type containing 13 (Guo et al. 2018a, b; Lence et al. 2016; Liu et al. 2014; Schwartz et al. 2014; Sledz and Jinek 2016; Warda et al. 2017). Recently, researchers have found that cells lacking fat mass and obesity-associated protein (FTO) lead to the up-regulation of m⁶A density in the 5’UTR region, indicating that FTO is an m⁶A demethylase (Zhou et al. 2015). In arabidopsis thaliana, AlkB homologue 10B (ALKHB10B) was also found to be m⁶A demethylase of mRNA (Jia et al. 2011; Zheng et al. 2013). The transferred methyl group can be recognized by different reader proteins, including YTH domain-containing family protein 1/2/3 (YTHDF1/2/3), YTH domain-containing protein 1/2 (YTHDC1/2), heterogeneous ribonucleoprotein (HnRNP), eukaryotic initiation factor 3 (eIF3), insulin-like growth factor 2mRN binding protein 1/2/3 (IGF2BP1/2/3), and proline-rich curl 2A (PRRC2A) (Alarcon et al. 2015; Hsu et al. 2017; Huang et al. 2018; Meyer et al. 2015; Shi et al. 2017; Wang et al. 2015; Xiao et al. 2016; Zhang et al. 2018). Studies have shown that YTHDF1 improves the translation efficiency of m⁶A-modified mRNAs (Wang et al. 2015). On the other hand, YTHDF2 mediates the instability and degradation of m⁶A-related mRNAs (Wang et al. 2014a, b). It has been demonstrated that other recognition proteins have different functions in m⁶A modified mRNA (Xiao et al. 2016; Shi et al. 2017; Kennedy et al. 2017a, b). Some studies focused on the distribution, function, and mechanism of RNA methylation modification, which provided a theoretical basis for disease-related research and aroused widespread concern in academic circles (Kennedy et al. 2017a, b; Willyard 2017) (Fig. 2).

Fig. 2.

The methylation-associated proteins of mRNA m⁶A. m⁶A methyltransferase, also referenced as the “writers”, its main function is to catalyze the RNA methylation process. The demethylase of m⁶A, also referred to as the “erasers”, can reverse the methylation modification that has been formed. The methylation binding protein is a reader of m⁶A, its main function is to selective bind m⁶A, affecting RNA transcription, splicing, nuclear export, translation, and stability. The m⁶A modificantion can participate in various biological functions, such as adult neurogenesis, neuron metabolism, learning and memory, motor function, and brain development

Histone Modifications and Chromatin Remodeling

Chromatin structure is dynamic, and the histone post-transcriptional modifier (PTM) usually regulates gene expression and cellular characteristics by regulating chromatin structure (Felsenfeld and Groudine 2003). At present, the research on histone modification is mainly focused on acetylation, methylation, and phosphorylation. However, histones can additionally be modified in different ways, including ubiquitination, formylation, and total acylation (Audia and Campbell 2016; Tan et al. 2011). The main target group of histone modification is histone octamer, which consists of four basic core histone H2A, H2B, H3, and H4, (Berger 2002; Dion et al. 2005; Govin et al. 2004; Kouzarides 2007). Histone methylation depends on the residues and the degree of methylation, and interactions with other modifications (Martin and Zhang 2005). Histone acetylation and histone phosphorylation are usually associated with transcriptional activation (Grunstein 1997; Imhof et al. 1997). Histone modification is dynamic and reversible process, which is regulated by acetyltransferase and deacetyltransferase, methyltransferase and demethylase (Kuo and Allis 1998; Trojer and Reinberg 2006). Recent studies have shown that JumonjiC (JmjC) family and lysine-specific demethylase (LSD) family can regulate the dynamic histone methylation. The LSD family can remove lysine labeling of monomethyl and dimethyl histones by FAD-dependent amine oxidase (Zheng et al. 2015). Proteins containing JmjC domains can hydroxylate lysine and arginine residues, which is needed for N-terminal histone methylation (Kooistra and Helin 2012). Researchers have found that JmjC proteins are associated with histone demethylation (Shmakova et al. 2014). Histone acetylation is mostly regulated by histone acetyltransferase (HATs) and histone deacetylase (HDAC) (Guo et al. 2018a, b). HDAC can mediate the elimination of acetyl groups on histone. HATs catalyze the addition of acetyl (de Ruijter et al. 2003) to lysine residues, thereby changing the structure of chromatin and forming the transcriptional active region of euchromatin. The dynamic balance of HAT/HDAC activity determines the histone acetylation level, thereby regulating the level of transcriptional (McKinsey et al. 2001). Ubiquitin is a polypeptide, which performs an essential role in cell DNA damage. Ubiquitination of histone H2A and H2B is a necessary post-translational modification in chromatin modification (Uckelmann and Sixma 2017). Polycomb repressive complex 1 (PRC1) can modify histone H2A at three different sites, including K13/K15, K119, and K127/129 sites. The monoubiquitylation of histone H2A C terminus (H2AK119ub1) is modified by K119 site, thereby regulating gene silence (Wang et al. 2004). Ubiquitin ligase Bre1 and ubiquitin-binding enzyme Rad6 can modify histone H2B in the gene coding region to produce the monoubiquitylation of the H2B C terminus (H2BK123ub1). H2BK123ub1 can regulate the initiation and extension of transcript (Fleming et al. 2008). Studies have shown that ubiquitination is an extremely dynamic modification. Isopeptidase, a deubiquitin enzyme, can remove ubiquitin modification, thereby regulating gene expression (Bannister and Kouzarides 2011). Sumoylation can occur in core histones and bind ubiquitin-like modifier molecules to histone lysine, thereby antagonizing ubiquitination and acetylation (Nathan et al. 2006; Seeler and Dejean 2003). However, further research is needed on the molecular mechanism of sumoylation.

Chromatin undergoes extensive remodeling during nuclear reprogramming. Genes, and more generally, chromatin are regulated by covalent modifications. The N-terminal amino acid residues of histone can be acetylated, methylated, or phosphorylated under the catalysis of various enzymes, to change chromatin structures, thereby activating or inhibiting gene transcription. There are two main structures that mediate chromosome remodeling: ATP-dependent nucleosome remodeling complex and histone modified complex. ATP can alter nucleosome structures through nucleosome remodeling and histone acetylation. Among chromatin modification factors, the heterogeneous nucleosome recombinant deacetylase (NURD) complex with ATP-dependent nucleosome remodeling and histone deacetylase activity has special research value.

Noncoding RNAs

Non-coding RNA includes long non-coding RNA (LncRNAs, transcription length more than 200 bp) and short non-coding RNA (transcription length less than 200 bp). LncRNAs can regulate gene expression via post-transcriptional pathways. Short non-coding RNA can affect chromatin structure, thereby regulating cell differentiation and gene expression (Aumiller and Forstemann 2008; Carissimi et al. 2009; Dharap et al. 2009; Jeyaseelan et al. 2008; Li et al. 2015; Merkerova et al. 2008; Sorensen et al. 2014). In addition, according to the classification of functions, non-coding RNA can be divided into two categories: one includes micronucleus RNA (snRNA), small nucleolus RNA (snoRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA), which are expressed in all types of cells and performs basic functions in cells. The other includes Piwi-related RNA (piRNA), circular RNA (circRNA), microRNA (miRNA), lncRNA, small interference RNA (siRNA), and tRNA derived small RNA (tsRNA). The most studied molecules are miRNA, lncRNA, and CircRNA (Ferlita et al. 2018).

Epigenetic Modifications and Motor Function

Effect of DNA Methylation on Motor Function

PD is characterized by bradykinesia, muscle rigidity, tremor, and paralysis. Recent studies have shown that epigenetic modifications are involved in the pathogenesis of PD. The expression of α-synuclein (SNCA) significantly changed in PD patients. The methylation of SNCA intron 1 decreased in substantia nigra and striatum of PD patients (Jowaed et al. 2010). This study shows that DNA methylation is involved in the regulation of SNCA levels, thereby inducing the pathogenesis of PD. In addition, the occurrence of PD is also related to the lack of DNMT1 (Desplats et al. 2011). Spinal muscular atrophy (SMA) is induced by the deletion or mutation of surviving motor neuron 1 (SMN1) gene, thereby impairing motor function (Lefebvre et al. 1995). Interestingly, the DNA methylation of SMN gene occurs in SMA patients, which is positively correlated with the severity of disease. (Hauke et al. 2009). Amyotrophic lateral sclerosis (ALS) is one of the fatal neurodegenerative diseases with no known genetic cause. Researchers conducted a genome-wide analysis of the midbrain in ALS patients and confirmed that various genes experienced abnormal DNA methylation (Morahan et al. 2007). In addition, Barry et al. reported that the expression of DNMT1 and DNMT3A increased in motor cortex and spinal cord motoneurons of ALS patients (Chestnut et al. 2011). In summary, these observations suggest that aberrant DNA methylation may be associated with neurodegenerative diseases.

Effect of m⁶A Modification on Motor Function

m⁶A is a widespread chemical modification in brain and involves in major biological processes (Meyer et al. 2012). m⁶A modification disorders are associated with neuronal developmental and degenerative diseases. Recent studies have found that FTO can regulate the occurrence and development of neurodegenerative diseases in motor neurons (Alunni and Bally-Cuif 2016; Engel and Chen 2018; Li et al. 2017). Hess et al. have demonstrated that inhibition of FTO can lead to the reduction of brain volume and the impairment of dopamine receptors (D2 and D3), which may be related to the pathogenesis of PD (Hess et al. 2013). Chen et al. have shown that the m⁶A modification of N-methyl-d-aspartate receptor 1 (NMDA1) mRNAs was downregulated in PD cells and animal models (Chen et al. 2019), which led to the apoptosis of dopaminergic neurons. These results suggest that m⁶A modification may be involved in the pathological process of PD. In addition, researchers have reported that the neuron-specific expression of FTO is highly expressed in motor neurons, and the outcomes of this study certified that FTO gene mutation may cause ALS (Mitropoulos et al. 2017). Therefore, the study of mRNA m⁶A modifications will provide a new target for the treatment of neurodegenerative diseases with dyskinesia.

Effect of Histone Modifications and Chromatin Remodeling on Motor Function

FTD-17 patients with Parkinson’s syndrome exhibits an abnormal accumulation of hyperacetylated microtubule-binding protein TAU in brain (Min et al. 2010). Researchers have shown that HAT-active elongation protein 3 (Elp3) is associated with motor neuron degeneration in ALS (Simpson et al. 2009). Furthermore, HDAC can influence the occurrence and development of ALS (Lazo-Gomez et al. 2013). The decrease of HDAC11 mRNA and the increase of HDAC2 mRNA were found in brain and spinal cord tissues of patients with ALS. (Janssen et al. 2010). Knockout of fusion sarcoma (FUS), a protein involved in motor neuron disease, can lead to the dislocation of HDAC1 (Scekic-Zahirovic et al. 2016). In a mouse model of superoxide dismutase (SOD1), the level of SIRT1 mRNA was increased in muscle, while the level of SIRT2 mRNA was decreased in motor neurons (Valle et al. 2014). In the same mouse model, researchers found that over-expression of HDAC6 delayed the impairment of motor neurons (Du et al. 2015). Studies have shown that the mechanisms of Friedreich ataxia (FRDA) and Huntington’s disease (HD) may involve abnormal histone modifications (Al-Mahdawi et al. 2008; Matsuda et al. 2019; Ryu et al. 2006). FRDA is mainly caused by GAA repetitive amplification mutation in intron 1 of the FXN gene. Researchers have shown that the histone acetylation level of ataxia gene was decreased, while the methylation level of histone H3 lysine 9 (H3K9) was increased in FRDA patients (Al-Mahdawi et al. 2008). HD is mainly caused by pathological prolongation of CAG repeat in exon 1 of Huntington gene (HTT). Some studies have found that HD may be related to the high methylation level of H3K9 and SETDB1HMT (Ryu et al. 2006). Abnormal histone methylation can reduce the levels of H3K27 trimethylation (H3K27me3) in medium spiny neurons, thereby interfering with gene expression (Matsuda et al. 2019). The deletion of polycomb inhibitory complex 2 (PRC2) and H3K27me2/3 will impaire motor performance, and the premature death of neuron (Kaneko et al. 2014; Kennerdell et al. 2018; Li et al. 2013; Piunti et al. 2019; Ragazzini et al. 2019; Sanulli et al. 2015; von Schimmelmann et al. 2016).

Researchers analyzed hundreds of human brain tissues and found that neuronal proteins undergo basic chromatin remodeling in brain (Weng et al. 2012). Hypermethylation of H3K9 and up-regulation of H2A1 (Hu et al. 2011) perform an essential role in the pathogenesis of HD (Stack et al. 2007). Frontotemporal dementia (FTD) is a neurodegenerative disease with sucking and grip reflexes in the early stage, myoclonus, pyramidal tract signs, and parkinson’s syndrome in the late stage (Bourinaris and Houlden 2018; Floris et al. 2015; Greaves and Rohrer 2019). TAR-DNA Binding Protein 43 (TDP-43), a DNA and RNA binding protein, can restrict the expression of chromatin remodeling factor CHD1 by forming insoluble aggregates (Berson et al. 2017; Chou et al. 2018; Fang et al. 2019; Gao et al. 2019; Stoica et al. 2014; Wang et al. 2018). Mass spectrometric analysis showed that the protein level of CHD2 significantly decreased in the temporal lobe cortex of FTD patients after death (Bennett et al. 2019; Che et al. 2018; Cobos et al. 2019). TDP-43 can regulate the protein level of Brama-associated gene 1 (BRG1) (Bronisz et al. 2014; Carey et al. 2016; Tibshirani et al. 2017), which is a component of neuronal BRG1-associated factor complex (nBAF), thereby regulating neuronal differentiation and function (Ronan et al. 2013; Shan et al. 2020; Son and Crabtree 2014; Staahl et al. 2013; Vogel et al. 2017). Therefore, abnormal chromatin remodeling may be one of the resons for the vulnerability of age-dependent neurons.

Effect of Noncoding RNAs on Motor Function

Compared with healthy subjects, 13 miRNAs (8 down-regulated, 5 up-regulated) were found to be associated with the pathogenesis of PD. U1, RP11-46 2G22.1 and RP11-79P5.3 were expressed in leukocytes, amygdala, and substantia nigra. RP11-462G22.1 is involved in muscular dystrophy, suggesting that it may be related to muscle rigidity in PD patients (Li et al. 2018; Soreq et al. 2014). The down-regulation of human accelerated regions 1 (HAR1, a lncRNA) is mediated by abnormal expression of HAR1F, thereby accelerating the pathogenesis of HD (Shimojo 2008; Wu et al. 2013; Zuccato et al. 2003). Taurine up-regulated gene 1 (TUG1, a lncRNA), a target of p53, may be associated with the development of HD (Ehrnhoefer et al. 2014; Intihar et al. 2019; Johnson 2012). In addition, the interaction between mutant Huntingtin and Argonaute 2 (AGO2), a member of Argonaute protein family, is involved in the regulation of gene silencing, which is mediated by miRNA (Savas et al. 2008; Tokiyoshi et al. 2018). Taken together, these findings suggest that noncoding RNAs are closely related to the pathogenesis of neurodegenerative diseases. A better understanding of noncoding RNAs will provide innovative ideas for exploring more effective strategies in the treatment of motor dysfunction (Table 1).

Table 1.

Epigenetic modifications in neurodegenerative diseases induced bradykinesia

Modifications	Examples of targets affected	Resulting disorders
DNA methylation	SNCA (SNCA intron 1 methylation); DNMTs (Changes in DNMT1 and DNMT3A levels);	PD, ALS, SMA
	SMN2 (SMN2 gene silencing)
N6-methyladenosine	FTO (FTO gene mutation); D2, D3 (The inhibition of FTO could damage to D2 and D3);	ALS, PD
	NMDA1 (Changes in NMDA1 expression levels)
Histone modifications	Tau (TAU hyperacetylation); ELP3 (Changes in ELP3 levels, which has HAT activity);	PD, ALS, FRDA, HD, Neurodegeneration
	HDACs (Changes in HDAC1/2/6/11 levels); SIRTs (Changes in SIRT1/2 levels); H3K9 (H3K9 methylation)
	SETDB1 HMT (Hypermethylation of SETDB1 HMT); PRC2 and H3K27me3 (Deletion of PRC2 and H3K27me2/3)
Chromatin remodeling	H3K9, H2A1 (Hypermethylation of H3K9 and up-regulation of H2A1);	HD, Age-dependent neuronal vulnerability
	TDP-43, CHD1/2, BRG1 (TDP-43 restricts the expression of CHDS and BRG1)
Noncoding RNAs	U1, RP11-46 2G22.1, RP11-79P5.3 (Changes in U1, RP11-46 2G22.1, and RP11-79P5.3 expression levels);	PD, HD
	HAR1 (Changes in HAR1 levels); TUG1 (Changes in TUG1 levels);
	AGO2 (AGO2 participates in the regulation of gene silence)

The Role of Epigenetic Drugs in Neurodegenerative Diseases

Over the recent years, due to their highly dynamic nature, epigenetic intervention can be used as a new therapeutic strategy for the treatment of neurodegenerative diseases, such as PD, HD, and ALS. Increasing research has proven that the HDAC inhibitor (HDACi), including trichostatin A, sodium butyrate, sodium phenylbutyrate, and valproic acid, can antagonize progressive neuronal degeneration in HD (Hockly et al. 2003; Tremolizzo et al. 2002). SNCA can inhibit histone acetylation, thereby producing neurotoxicity. Researchers have shown that valproic acid could counteract the neurotoxicity of SNCA and improve the symptoms of PD dyskinesia (Coppede 2014). Furthermore, severa studies have revealed that SNCA-induced neurotoxicity of PD can be antagonized by the administering sodium butyrate or inhibiting of histone deacetylase SIRT2 (Coppede 2014; Outeiro et al. 2007). In HD, anthracycline can improve the acetylation dysfunction of H3 and H4 histones and the hypermethylation of H3K9 (Valor 2015). Recent studies have shown that cysteamine and mithramycin treatment can reduce the hypermethylation of H3 and improve the survival rate of HD patients (Wang et al. 2014a, b). Phenylbutyrate, a type of HDACi, can improve the ALS-associated symptoms of motor dysfunction (Valor 2015; Cudkowicz et al. 2009). Restoring the expression of SAM in ALS can improve neuronal dysfunction (Suchy et al. 2010). At present, several HDACis, DNMTs inhibitors, LSD1 inhibitors, histone methyltransferase dot1-like protein, and enhancer of zeste homolog 2 inhibitors have entered the clinical trial stage (Hsieh and Gage 2005; Audia and Campbell 2016). To treat neurodegenerative diseases, further research is needed on related epigenetic drugs research to overcome neurodegenerative diseases.

Conclusion

Epigenetic modifications have attracted people’s attention in the fields of medicine and pharmacy. Abnormal epigenetic modifications can induce neurodegenerative diseases and motor dysfunction by regulating the expression of different genes (Marques et al. 2011; Migliore and Coppede 2009). Intervention of epigenetic modifications has provide new targets for the treatment of neurodegenerative diseases (Abel and Zukin 2008; Chuang et al. 2009; Dietz and Casaccia 2010; Hahnen et al. 2008; Kazantsev and Thompson 2008; Konsoula and Barile 2012). Collectively, these outcomes suggest that epigenetic modifications perform a crucial role in neurodegenerative diseases, it may be acting as a driver. Abnormal epigenetic modifications can not only lead to motor dysfunction, but also to learning and memory impairment, further research is needed on related epigenetic mechanisms.

The regulatory factors related to epigenetic modifications may be suitable as targets for the direct treatment of neurodegenerative diseases. However, in order to further understand and prove the role of epigenetic modifications in neurodegenerative disorders, many problems still need to be resolved. For example, what is the specific molecular mechanism that causes disease; whether there are other diseases related to it; how the body selects specific mRNA for methylation modification; and whether there are other proteins involved in the formation of disease. It is worth noting that different diseases can interact with different regulatory proteins and different cells have different regulators to affect the expression of specific mRNA. However, there are relatively few animal models and cell models to elucidate the pathogenesis, biochemical disorders, and morphological changes of neurodegenerative diseases. This requires further exploration to clarify how epigenetics regulate motor function through the stimulation of external environment, drugs, and poisons, so as to fully reveal the role of epigenetic modifications on neurodegenerative disorders. This paper will provide new ideas and new therapeutic potential of epigenetic drugs in neurodegenerative diseases with dyskinesia.

Abbreviations

AGO2

Argonaute 2

ALS

Amyotrophic lateral sclerosis

ALKHB5/10B

AlkB homolog 5/10B

BRG1

Brahma-related gene 1

circRNA

Circular RNA

CNS

Central nervous system

CpG

Cytosine-phosphate-guanine

D2

Dopamine receptor 2

D3

Dopamine receptor 3

DNMT

DNA methyl-transferase

ELP3

Elongator protein 3

eIF3

Eukaryotic initiation factor 3

FRDA

Friedreich ataxia

FTD

Frontotemporal dementia

FTO

Fat mass and obesity-associated protein

FUS

Fused in sarcoma

HATs

Histone acetyltransferases

HDACs

Histone deacetylases

HD

Huntington’s disease

HDACi

HDAC inhibitor

H3K9

Histone H3 lysine 9

HnRNP

Heterogeneous nuclear ribonucleoprotein

IGF2BP 1/2/3

Insulin-like growth factor 2 mRNA-binding protein 1/2/3

JmjC

Family and members of the Jumonji C

lncRNAs

Long noncoding RNA

LSD

Lysine-specific demethylase

m⁶A

N6-Methyladenosine

METTL3/14/16

Methyltransferase like 3/14/16

miRNA

MicroRNA

nBAF

Neuronal BRG1-associated factor complex

NMDA

N-methyl-d-aspartate

NURD

Nucleosome remodeling histone deacetylase

PD

Parkinson’s disease

piRNA

Piwi related RNA

PRC2

Polycomb-repressive complex 2

PTM

Post-transcriptional modifier

PRRC2A

Proline rich coiled-coil 2A

rRNA

Ribosomal RNA

siRNA

Small interfering RNA

SMA

Spinal muscular atrophy

SMN1

Survival motor neuron 1

SNCA

α-Synuclein

snRNA

Small nuclear RNA

snoRNA

Small nucleolar RNA

tRNA

Transfer RNA

SOD1

Superoxide dismutase

SIRT

Sirtuins

TDP-43

TAR-DNA Binding Protein 43

TET

Ten-eleven translocation

tsRNA

TRNA derived small RNA

TUG1

Taurine-upregulated gene 1

YTHDF1/2/3

YTH domain-containing family protein 1/2/3

YTHDC1/2

YTH domain-containing protein ½

5caC

5-Carboxylcytosine

5hmC

5MC to 5-hydroxymethylcytosine

5mC

5-Methylcytosine

Author contributions

Each author substantially contributed to the review. ZQ: conception and design, drafting the manuscript; JL, ML, XD, LZ, SW, BX, WL, and ZX: revising the manuscript; YD: conception and design, revising it critically for important intellectual content, and final approval of the version to be published. All authors read and approved the final manuscript.

Funding

We gratefully acknowledge funding from the Natural Science Foundation of Liaoning Province [2020-MS-152], the Basic Research Fund of Young Program of Higher Education of Liaoning Province (Grant No. QNK201735), the National Natural Science Foundation of China (Grant No. 81302406) and the Funds for Distinguished Young Scientists in School of Public Health, China Medical University.

Data Availability

Not applicable.

Code Availability

Not applicable.

Declarations

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

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Consent to Participate

Not applicable.