Emerging roles of epigenetic mechanisms in Parkinson’s disease
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- Habibi, E., Masoudi-Nejad, A., Abdolmaleky, H.M. et al. Funct Integr Genomics (2011) 11: 523. doi:10.1007/s10142-011-0246-z
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Epigenetic mechanisms have emerged as important components of a variety of human diseases, including cancer and central nervous system disorders. Despite recent studies highlighting the role of epigenetic mechanisms in several neurodegenerative and neuropsychiatric disorders, to date, there has been a paucity of studies exploring the role of epigenetic factors in Parkinson’s disease (PD). PD is a progressive neurological disorder with characteristic motor and non-motor symptoms, including a range of neuropsychiatric features, for which neither preventative nor effective long-term treatment strategies are available. It is one of the most common neurodegenerative disorders and the second most prevalent after Alzheimer’s disease. In this review, we present several lines of evidence suggesting that epigenetic factors may play an important role in the pathogenesis of PD and propose on this basis a framework to guide future investigations into epigenetic mechanisms and systems biology of PD. These notions, together with technical advances in the ability to perform genome-wide analysis of epigenomic states, and newly available small-molecule probes targeting chromatin-modifying enzymes, may help design new treatment strategies for PD and other human diseases involving epigenetic dysregulation.
KeywordsParkinson’s diseaseEpigeneticsNeurodegenerative disordersNeurodevelopmental disordersPsychiatric disordersSystems biology
Parkinson’s disease (PD) is a progressive neurological disorder for which neither preventative nor effective long-term treatment strategies are available. It is one of the most common neurodegenerative disorders and the second most prevalent after Alzheimer’s disease with close to 3 million people in Europe and North America comprising 1–2% of the population over 65 years of age (Gasser 2009a; Mena et al. 2008). Accordingly, the treatment of PD presents a serious challenge to health care systems and society worldwide and area for which novel therapeutic options are critically needed.
PD is characterized by a number of motor and non-motor symptoms (Jankovic 2008). Approximately, 50–80% of neurons in the pars compacta region of the substantia nigra (SNpc), which produces the neurotransmitter dopamine, are known to degenerate in PD (Jankovic 2008; Lesage and Brice 2009). Along with the loss of the dopaminergic neurons of the SNpc, the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies is a pathological characteristic of most but not all forms of PD (Conway et al. 2000). The loss of the SNpc neurons causes degeneration of the nigrostriatal tract and pathological alterations in neurotransmission in the basal ganglia motor circuit, leading to the classic motor symptoms of PD including tremor, rigidity, bradykinesia, and postural instability (Jankovic 2008; Johnson et al. 2009). As a result, affected patients have diminished control and problems coordinating their movements.
In addition to motor features, characteristic non-motor features of PD include neuropsychiatric disturbances such as cognitive deficits, mood disturbances (depression, apathy, and anxiety), and obsessive–compulsive behaviors. Other non-motor features include sleep disturbances, ophthalmologic abnormalities, and gastrointestinal autonomic and problems, many of which are thought to result from dopaminergic imbalance (Brandabur 2007; Jankovic 2008).
The etiology of PD still remains poorly understood. PD incidence has been shown to grow with increased age (Tanner et al. 1999), with evidence for both environmental and genetic risk factors playing important roles (Gasser 2009b; Mena et al. 2008). While a number of genes have been identified for rare monogenic forms of PD, these genes provide an incomplete picture of the disease process. Currently, more than 13 loci and nine genes have been shown to cause Mendelian forms of PD (Lesage and Brice 2009), including α-synuclein (SNCA), parkin (PARK2), leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), DJ-1 protein (DJ-1), and PTEN-induced kinase protein 1 (PINK1). SNCA and LRRK2 mutations have been shown to cause PD through a dominant, toxic gain-of-function mechanism, whereas PARK2, DJ-1, and PINK1 mutations do so through a recessive, loss-of-function mechanism (Gasser 2009b).
Besides genetic factors, there is evidence that certain non-genetic, environmental factors play critical roles in development of several neurological disorders. As an example of non-genetic factors that can lead to PD, in the 1980s, it was found that exposure to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), resulted in PD-like symptoms (Hubble et al. 1993). In addition to MPTP, other environmental toxins, including paraquat and rotenone, and other factors that cause mitochondrial dysfunctional, have been associated with increased risk of developing PD, although a clear causal role remains debated (Franco et al. 2010).
Epigenetics can be summarized to include the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states (Bird 2007). The following sections provide an overview of two major types of epigenetic mechanisms that may contribute to the development of PD.
DNA methylation plays a crucial role in the long-term repression of gene expression and in the formation of heterochromatic regions (Miranda and Jones 2007). In mammals, this covalent modification is the addition of methyl (CH3) groups to the 5′ position of cytosine residues within CpG dinucleotides, a reaction catalyzed by DNA methyltransferases (DNMTs) with the contribution of S-adenosyl-methionine as the major methyl donor. De novo methylation is catalyzed by de novo methylases DNMT3a and DNMT3b. DNMT1, the maintenance methylase, is active on the replication fork during DNA replication to maintain the established methylation patterns by de novo methylases (Abdolmaleky et al. 2008; Miranda and Jones 2007). In contrast to unmethylated dinucleotide clusters of CpGs in CG-rich regions of genomes, CpG islands located at promoters and untranslated regions, as well as exon 1 of around 40% of mammalian genes, the rest of CpG dinucleotides in other regions of the mammalian genome are mostly methylated (Takai and Jones 2002; Miranda and Jones 2007). On the whole, dense DNA methylation at promoters is associated with gene repression, whereas unmethylated promoters are mostly linked to gene activation (Jiricny and Menigatti 2008). DNA methylation has been shown to cause gene repression by: (a) physically inhibiting the binding of specific transcription factors to CG-containing sequences, such as stimulatory protein 1 (SP1) and cAMP response element binding protein; and (b) recruitment of methyl binding domain proteins, which are part of large multiprotein complexes composed in part by a number of histone-modifying enzymes (Miranda and Jones 2007; Abdolmaleky et al. 2008).
Post-translational histone modifications
In order to package the eukaryotic genome, DNA is packaged into a highly compact structure through charge interactions between positively charged histone tails and negatively charged DNA and between histone tails of neighbor nucleosomes. The nucleosome is the building block of chromatin that is composed of an octamer of the four highly basic core histones (H3, H4, H2A, and H2B) plus a linker histone (H1) around which 147 base pairs of DNA are wrapped. The accessibility of DNA template to the transcription machinery and other chromatin-associated factors is restricted by nucleosome structure and location on DNA.
To provide regulated access to DNA templates in chromatin and create reversible epigenetic states, nature has developed a number of mechanisms most notably those that involve the unstructured N-terminal tails of the core histones that protrude from each nucleosome in all directions. These N-terminal tails are 25–40 residues in lengths and provide a surface for chromatin-modifying enzymes, including ATP-dependent chromatin-remodeling complexes and histone-modifying complexes that add or remove different types of posttranslational modifications (PTMs) from histones. To date, the PTMs identified on histones include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, ADP, and ribosylation. Collectively, PTMs on histone mediate chromatin-related processes in at least three ways: (a) neutralizing and reducing the interaction of the positively charged amino acid residues to negatively charged DNA, (b) disrupting interactions between neighbor histone tails, and (c) creating a binding site for specialized proteins containing domains that bind to post-translationally modified residues (Narlikar et al. 2002; Sterner and Berger 2000). In the latter two cases, a growing number of studies have demonstrated that modified residues serve as docking sites to recruit various types of proteins such as other chromatin-modifying enzymes and transcription factors regulating gene transcription (Kouzarides 2007; Li et al. 2004; Spencer and Davie 1999; Grant 2001; Allis et al. 2007). Combinatorial sets of histone modification on one or more histone tails constitute have been shown to regulate distinct downstream events including transcriptional state (Jenuwein and Allis 2001; Strahl and Allis 2000; Taverna et al. 2007; Turner 2002).
Role in transcription regulation
PCAF/Gcn5, STAGA, TFTC
H3 (K9,K14,K18,K23, K27) H4 (K5,K8,K12,K16) H2A (K5, K9, K13) H2B (K5,K12,K15,K20)
TIP60, HB01, MOZ/MORF
Histone deacetylases (HDACs)
HDAC 1, 2, 3, 8
HDAC 4, 5, 6, 7, 9, 10, 11
Class III (sirtuins)
Lysine methyltransferases (KHMTases)
SET domain containing KHMTases
SUV39, SET1, SET2, EZH, SMYD, PRDM
H3 (K4,K36,K79) H3 (K9,K27), H4 (K20)
CARM1, PRMT4 PRMT5
H3 (R2, R17, R26), H4 (R3) H3 (R8), H4 (R3)
H3 (K4, K9, K36)
Jumonji (JmjC) domain proteins
FBXL (KDM2), JMJD1 (KDM3), JMJD2 (KDM4), JARID1 (KDM5), UTX/JMJD3 (KDM6), JARID2 (Jumonji), PHD finger (PHF), HSPBAP1, Arginine demethylases
Haspin, MSK1, MSK2, CKII, Mst1
H3 (S10, S28, T3, T11) H4S1, H2AS1, H2BS14
RNF20/RNF40, UbcH6 Bmi/Ring1A
H2B (K123) H2A (K119)
E1 (SAE1and SAE2) E2 (UBC9) E3 (e.g. PIAS family proteins, RanBP2, The polycomb protein Pc2)
H3 (?) H4 (K5,K8,K12,K16) H2A (K126) H2B (K6,K7,K16,K17)
MARTs (Mono-ADP-ribosyltransferases), PARPs (poly-ADP-ribose polymerases), Sir family
Histone methylation can occur either at certain lysine or at arginine side chains on the N-terminal tails of H3 and H4 (Fig. 1). Methylation has some properties that make it more complicated than other histone covalent modifications. In addition to its occurrence on lysine and arginine, depending on the site of the residue on the histone tail, the effect of methylation on gene transcription can be either positive (e.g., H3K4, 36, 79; H3R2, 17, 26, and H4R3) or negative (e.g., H3K9, 27, and H4K20; H3R8 and H4R3). Furthemore, the degree of methylation on each residue, mono- or di-methylated states on arginines and mono-, di-, or tri-methylated states on lysines, add an additional layer of complexity to the role of histone methylation in gene expression. In addition, the dimethylated state of the arginine residue can be in symmetric or asymmetric configurations, which has been associated with different functional consequences on gene expression (Fig. 1). Lysine residues are methylated by two families of SET domain and non-SET domain-containing histone lysine methyltransferases, which respectively act on certain lysines residues in the N-terminal tails of H3 and H4 with arginine residues methylated by the PRMT protein family.
Similar to histone acetylation, it is now recognized that histone methylation is also a reversible and dynamic process (Shi et al. 2004; Klose and Zhang 2007). Two families of histone demethylases (KDMs) have been identified, including the amine oxidase domain-containing KDM1A (LSD1) and Jumonji C (JmjC) domain-containing protein family. A characteristic feature of most KDMs is the presence of additional domains, including zinc fingers (e.g., PHD finger) involved in DNA, RNA, and protein interactions, F-box domains involved in protein interactions, paired Tudor domains that bind methylated histones. Lysine specific demethylase 1 (LSD1 also known as KDM1A, BHC110, and AOF2), the first identified histone demethylase, depending on interacting partners, selects its substrate and removes the methyl groups from methylated lysine 4 of histone H3 (H3K4) and lysine 9 of histone H3 (H3K9) (Forneris et al. 2005; Nicholson and Chen 2009; Shi and Whetstine 2007). LSD1 is present as a subunit of both repressive (CtBP, CoREST, NURD/Mi2/NRD, and BRAF35-HDAC complexes) and activating complexes (Hakimi et al. 2002; Khochbin and Kao 2001; Nicholson and Chen 2009; Shi et al. 2004; Shi et al. 2005; Wang et al. 2009). For instance, in association with a repressive complex like CoREST, LSD1 acts as an H3K4me2/me1 demethylase and results in repression of transcription. In contrast, binding with the androgen receptor, LSD1 demethylates H3K9me2/me1 resulting in transcriptional activation (Cloos et al. 2008; Shi et al. 2004).
Other histone modifications
Other types of histone modifications, such as phosphorylation, sumoylation, and ubiquitylation, also play important roles in the dynamic regulation of gene transcription. For example, it has been shown that phosphorylation of H3S10 and linker H1 may regulate gene expression. Sumoylation is known as a repressive modification; however, the effect of ubiquitylation on transcription can be activating or repressing. Ubiquitylation of H2AK119 and H2BK123 are associated with transcriptional repression and activation, respectively (Allis et al. 2007) (Table 1).
Evidence linking epigenetic mechanisms to Parkinson’s disease
Epigenetic alternations reported in neurodegenerative and neurodevelopmental disorders
Human cell culture (Cao and Sudhof 2001)
Murine neuronal culture (Rouaux et al. 2003)
Aged monkey (Wu et al. 2008)
Human cell ⁄murine neuronal culture (Marambaud et al. 2003)
PS1 mouse model (Saura et al. 2004)
Human cerebral cortex (Siegmund et al. 2007)
Human cerebral cortex (Siegmund et al. 2007)
Murine cerebral endothelial cells model (Chen et al. 2009)
Human neuroblastoma cell lines (Belyaev et al. 2009)
p25 ⁄ Cdk5 mouse model (Kim et al. 2007)
p25 ⁄ Cdk5 mouse model (Fischer et al. 2007)
Human cell culture ⁄Drosophila model (Steffan et al. 2001), Human cell culture (Sugars et al. 2004), R6 ⁄ 2 and 82Q mouse models (Ferrante et al. 2004; Gardian et al. 2005; Hockly et al. 2003; Stack et al. 2007) R6 ⁄ 2 and 82Q mouse models (Stack et al. 2007)
Human patients (Pieper et al. 2008)
MeCP2 mouse models (Shahbazian et al. 2002)
Murine cell culture (Martinowich et al. 2003)
Fragile X syndrome
Human patients (in response to valproate)
Epigenetic mechanisms implicated by PD models and existing therapeutic agents
In two different models of MPTP-induced PD, dopamine depletion was associated with a reduction in H3K4me3 in striatal histones, whereas chronic levodopa therapy leads to deacetylation of histones H4K5, K8, K12, and K16 (Nicholas et al. 2008). Consistent with these findings of epigenetic changes, genome-wide expression profiling studies in the 6-hydroxydopamine model of PD (Konradi et al. 2004) have reported numerous changes in gene expression with changes including both upregulated and downregulated genes. Taken together, these findings point to the dynamic regulation of multiple genes by factors affecting PD.
Another potential example of existing therapeutics agents for PD affecting epigenetic states is that of monoamine oxidase (MAO) inhibitors (MAOIs), which are used for the treatment of depression, anxiety, and PD (Gooden et al. 2008). It has been demonstrated that blockage of MAO enzymes with tranylcypromine prevents the death of dopaminergic neurons caused by the exposure of nigral dopaminergic neurons of rat to an otherwise toxic mixture of thrombin and dexamethasone (Arguelles et al. 2010). Tranylcypromine (trans-2-phenylcyclopropylamine, 2-PCPA, Parnate), a type of antidepressant known as a nonselective MAOI, has been shown to be an inhibitor of LSD1 (Mimasu et al. 2008). In addition to demethylating histones, LSD1 demethylates dimethylated p53-K370 and suppresses p53 transcriptional activity (Huang et al. 2007b). p53 demethylation prevents its interaction with its transcriptional co-activator 53BP1 to induce apoptosis (Cloos et al. 2008; Huang et al. 2007b; Scoumanne and Chen 2007, 2008; Tsai et al. 2008). Regarding the level of p53 expression in PD patients, studies have shown noteworthy results (Jellinger 2000; Levy et al. 2009; Mogi et al. 2007; Nair et al. 2006). In one study, p53 levels in nigrostriatal dopaminergic brain regions was significantly increased in PD patients in comparison with controls, whereas no significant change was observed in the SNpc region (Mogi et al. 2007). In another study, Nair et al. (2006) showed that the active (phosphorylated) form of p53 was increased in the SNpc of post-mortem PD brains. Other types of MAO inhibitors frequently used in PD, such as selegiline, which also has LSD1 inhibitory activity, have been shown to have anti-apoptotic activity and decreases apoptosis in vitro (Jie et al. 2009). Additional studies are required to determine precisely the role of LSD1 in PD etiology and pathophysiology.
α-Synuclein histone acetylation, DNA methylation/demethylation, and transcriptional regulation
Misfolded α-synuclein bound to ubiquitin forms a complex that cannot be transferred to the proteasome and aggregates in cytoplasmic inclusions called Lewy bodies. These inclusions may be a cause of the midbrain dopaminergic neuron loss in substantia nigra (Migliore and Coppede 2009), although the precise mechanism through which this occurs is unknown. Following the accumulation of α-synuclein in the neurons, it forms a complex including ERK2 and ELK1, which leads to inappropriate inhibition of MAP kinase pathway, which will affect the function of a variety or transcription factors and other cellular regulators. Therefore, dysfunction of MAP kinase pathway might be a cause of neuron loss and neurodegeneration in PD (Iwata et al. 2001). Recently, it has been demonstrated that DNA methylation of human SNCA intron 1 and demethylation of the SCNA CpG in brains of PD patients can regulate SNCA gene expression (Jowaed et al. 2010; Matsumoto et al. 2010). Alternatively, or in addition, nuclear α-synuclein through direct interaction with histones, decreases histone H3 acetylation (Kontopoulos et al. 2006). In vitro cell culture and Drosophila studies have shown that familial PD mutations in α-synuclein (A30P and A53T) cause increased nuclear targeting of α-synuclein in cultured cells (Kontopoulos et al. 2006). α-Synuclein has been shown to bind to histones and HATs and inhibits acetylation in HAT assays (Kontopoulos et al. 2006). Consistent with these findings, administration of class I HDAC inhibitors, such as SAHA (Vorinostat) and sodium butyrate, ameliorate α-synuclein-induced neurotoxicity as well as have neuroprotective properties in neurotoxin models of PD-related neurodegeneration (Abel and Zukin 2008; Gardian et al. 2004; Kontopoulos et al. 2006; Leng and Chuang 2006).
In terms of target genes potentially affected by epigenetic dysregulation in PD, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is known to play a key role in the growth, survival, synaptic plasticity, and maintenance of neurons. Reduction of BDNF levels in neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and PD has been reported (Zuccato and Cattaneo 2009), and BDNF expression is regulated by histone acetylation as well as DNA methylation (Martinowich et al. 2003). In the substantia nigra pars compacta of PD-affected neurons, the amount of BDNF mRNA expression is decreased. It has been suggested that pathogenic α-synuclein mutations, A30P or A53T, may be linked to the loss of BDNF (Kohno et al. 2004; Zuccato and Cattaneo 2009), whereas HDAC inhibitors may rescue BDNF expression by increasing BDNF expression.
Recently, inhibition of the SIRT2 NAD-dependent lysine deacetylase was shown to protect against α-synuclein-mediated toxicity in vitro in cellular models and in a Drosophila model of PD (Outeiro et al. 2007b). However, the mechanism through which inhibition of SIRT2 provides neuroprotection remains poorly understood, although most recent studies suggest this is through a non-nuclear/histone-mediated effect involving regulation of sterol biosynthesis (Luthi-Carter et al. 2010).
Nurr1, Pitx3, CoREST/NCoR/SMRT, and histone-modifying complexes
The transcription factor Nurr1, which plays a key role in the development and maintenance of the midbrain dopamine cells, may play a part in the pathogenesis of PD and provide an important link to chromatin-modifying complexes (Jankovic et al. 2005). It has been shown that expression of Nurr1 is significantly reduced in patients affected with PD (Le et al. 2008). The CoREST repressor complex, which plays a critical role in Nurr1-mediated transcriptional repression, recruits a group of proteins consisting of HDACs, the histone methyltransferase G9a and LSD1, which target promoters leading to transcriptional repression (Saijo et al. 2009). It has also been shown that cocaine consumption decreases Nurr1 expression in dopamine neurons. In addition, in the dopamine neurons of Nurr1-deficient cocaine abusers, the expression of the dopamine transporter (DAT) is significantly decreased (Bannon et al. 2002). DATs, which are located in the membrane of dopaminergic neurons in the SNpc, are strikingly reduced in PD likely due to degeneration of these cells (Bannon et al. 2001). Similar to Nurr1, another transcription factor that has been shown to be important for midbrain dopamine neuron development is Pitx3 (paired-like homeodomain transcription factor 3 or pituitary homeobox 3). Pitx3 restores Nurr1 from a SMRT-mediated repressed state. As mentioned above, the multiprotein, co-repressor NCoR/SMRT-HDAC3 complex keeps promoters in a deacetylated state to represses gene transcription (Jacobs et al. 2009; Li et al. 2009).
In terms of potentially relevant target genes negatively regulated by these co-repressor complexes in midbrain dopamine neurons, the transcription of the p57Kip2 gene appears to be negatively regulated by LSD1 (Shi et al. 2004). Besides its known function in control of proliferation, p57Kip2 affects postmitotic differentiation of midbrain dopaminergic neuronal cells. Expression of p57Kip2 is regulated by Nurr1 through a direct protein–protein interaction (Joseph et al. 2003). COUP-TF-interacting protein 2 (CTIP2) recruits the NuRD complex including HDAC1 and HDAC2 to the promoter of the p57Kip2 gene (Topark-Ngarm et al. 2006). CTIP2 through recruiting SIRT1, HDAC1, and HDAC2 leads to transcriptional repression, and it has been shown that HDAC inhibitors increase p57Kip2 transcript levels (Topark-Ngarm et al. 2006). In animal models of Alzheimer’s disease and Huntington’s disease, SIRT1 expression diminishes neuronal degeneration, and thus, its activity could be neuroprotective for PD. Nonhistone substrates of SIRT1 include p53, NF-κB, and FOXO family of forkhead transcription factors. By deacetylating p53, SIRT1 binds and suppresses p53-mediated transactivation and p53-dependent cellular apoptotic in response to DNA damage and oxidative stress. SIRT1 directly interacts with RelA/p65 subunit of NF-κB and inhibits its transcriptional activity by deacetylation at Lys310. Inhibition of NF-κB causes TNF-α induced apoptosis (Tang and Chua 2008; Yeung et al. 2004). In addition, SIRT1 inhibits the transcriptional activity of c-Jun through direct physical interaction (Gao and Ye 2008).
CoREST, G9a, and cocaine
Additional roles for co-repressor complexes containing CoREST and histone-modifying enzymes are highlighted by considering the effect of cocaine on dopaminergic signaling. Cocaine has been shown to render neurons in SNpc more sensitive to exposure to environmental toxins, which may lead to PD. Based on the duration of exposure to cocaine, different genes are activated or repressed. After acute exposure, the level of G9a is increased, and binding of G9a to the fosB gene becomes greater than before. In contrast, after chronic cocaine exposure, the transcription factor ΔFosB binds to the promoter of lysine methyltransferase G9a, which dimethylates H3K9, leading to repression of its expression (Renthal and Nestler 2008; Maze et al. 2010). Consequently, by decreasing G9a expression, binding of G9a to the fosB gene is reduced. As well, after chronic cocaine exposure, ΔFosB binds to certain promoters like cdk5 and bdnf and recruits transcriptional activators and activates these genes where H3 acetylation is increased. By comparing differential gene expression in PD SNpc versus healthy controls, CDK5 shows significant differences in expression (Yang et al. 2009a). Therefore, by considering the role of cocaine in regulation of histone modifications, it is possible to imagine roles for epigenetic regulation of these genes involved in the etiology of PD.
UCHL1 and DNA methylation
UCHL1 is a well-known candidate gene associated with PD (Inzelberg and Jankovic 2007). Inactivation of the UCHL1 by CpG hypermethylation of its promoter is associated with liver cancer and several digestive carcinomas. However, DNA methylation analysis of UCHL1 gene in α-synucleinopathies has shown no differences between unaffected and affected cases in PD and dementia with Lewy bodies pure (DLBp) and common forms (DLBc), although further study on affected brain nucleus is required to reach to a conclusive determination of a potential role for DNA methylation in UCHL1 regulation (Barrachina and Ferrer 2009).
BCOR complex and polycomb group proteins
Recently, it has been shown that SKP1A, a component of the SKP1–Cullin 1–F-box protein ubiquitin ligase complex, which plays an important role in DA neuron survival, is highly reduced in the SNpc of postmortem brains in sporadic PD (Fishman-Jacob et al. 2009; Mandel et al. 2007). SKP1 along with Polycomb group (PcG) proteins are found in the BCOR (BCL6 co-repressor) complex. PcG proteins consist of RING1 (Ring1a), RYBP, NSPC1, and RNF2 (Ring1b). RNF2 E3 ligase is the core member of PcG proteins and catalyses mono-ubiquitylation of H2A. H2AK119ub1 is a repressive histone mark that in turn through cross-talk mechanisms affects with H3K4me2, H3K4me3, and H3S10 phosphorylation levels (Joo et al. 2007; Zhou et al. 2009). Existence of two different types of ubiquitin E3 ligases (RNF2 and SKP1) and histone demethylase FBXL10/JHDM1B in the BCOR complex suggests that as a transcriptional co-repressor, it employs a unique combinatorial pattern of epigenetic marks for gene silencing (Gearhart et al. 2006). It has been demonstrated that F-box protein FbXL10/JHDM1B, a histone demethylase that demethylates H3K4me3, through interaction with c-Jun, represses c-Jun-mediated transcription (Koyama-Nasu et al. 2007). These lines of evidence may provide a clue as to how a defect in each components of BCOR complex can cause a problem and even how it can have an influence on the function of other components involved in the survival of DA neurons.
MEF2D, CDK5, and HDAC4
Cdk5 has a pivotal role in degeneration of dopamine neuron loss in PD. Following MPTP treatment, subsequent induction of calpain results in cleavage of p35/Cdk5 to p25/Cdk5, and this cleavage increases the activity of Cdk5 in the substantia nigra. Consequently, activation of Cdk5/p25 leads to nuclear MEF2D (myocyte enhancer factor 2D) phosphorylation and its degradation by caspase-3 (Camins et al. 2006; Smith et al. 2006; Tang et al. 2005). It has been suggested that HDAC4 binds to MEF2D and represses its transcriptional activity by local histone deacetylation. Although HDAC4 does not deacetylate MEF2D, SIRT1 plays a role as a MEF2D deacetylase. MEF2D acetylation and sumoylation are associated with activation and repression of transcriptional activity, respectively. Modification of MEF2D at Lys439 by the acetyltransferase CBP and SUMO E3 ligase Ubc9 shows a dynamic interplay between acetylation and sumoylation in transcriptional regulation of this factor (Zhao et al. 2005). It has been observed that in the brains of transgenic mice affected with PD, the levels of MEF2D are raised (Yang et al. 2009b). Human MEF2D is post-translationally modified on Ser-444 and Lys-439 by phosphoryl and sumoyl groups, respectively. Phosphorylation of Ser-444 by Cdk5, which is stimulated by the class IIa HDAC4, is a prerequisite for sumoylation and represses transcriptional activity of MEF2D (Gregoire et al. 2006). Sumoylation is catalyzed by the SUMO E2-conjugating enzyme Ubc9 (Zhao et al. 2005).
JNK, c-Jun, and Eg5
Another example of transcriptional regulation under control of PD risk genes is that of Eg5, a motor protein of the kinesin family, whose transcription is repressed by Parkin. Parkin plays this role by blocking c-Jun binding to the AP1 site existing in the Eg5 promoter. Parkin reduces c-Jun activation through inactivation of c-Jun NH2-terminal kinase (JNK). In addition, it has been shown that monoubiquitination of Hsp70 is essential for parkin to inactivate JNK and to downregulate Eg5 expression by blocking c-Jun binding to the AP1 site existing in the Eg5 promoter (Liu et al. 2008).
Histone kinases and PD
Casein kinase II (CKII) is a serine/threonine kinase that phosphorylates histone H4 serine 1 in response to DNA damage (Cheung et al. 2005). CKII can also phosphorylate synphilin-1, reducing its interaction with α-synuclein and formation of inclusion bodies. In addition, CKII phosphorylates Ser-129 of α-synuclein in human brain and inhibits Cdk5. Because synphilin-1 phosphorylation does not affect its ubiquitylation, it has been proposed that the formation of synphilin-1 inclusions not only needs ubiquitylation but also requires other factors such as interaction with α-synuclein and phosphorylation (Ishii et al. 2007; Lim et al. 2004; Szargel et al. 2008).
PARP-1, aurora-B kinase, and p53
It has been proposed that (ADP-ribose) polymerase-1 (PARP-1), which interacts with transcription factors such as NF-κB, SP1, and p53, plays a role in neurodegeneration (Oei et al. 1998). (Outeiro et al. 2007a). It has been suggested as well that α-synuclein by activation of NOS and releasing NO considerably reduces PARP-1 (Adamczyk and Kazmierczak 2009). Activation of PARP-1 in response to DNA damage inhibits aurora-B kinase, which is required for H3S10 phosphorylation (Monaco et al. 2005). Activation of PARP-1 also results in poly(ADP-ribosyl)ation of p53. The resulting modified p53 cannot interact with Crm1 and its accumulation stimulates increased transcription of p21 (Alvarez-Gonzalez 2007), whereas in healthy cells, export of p53 from the nucleus into the cytoplasm toward ubiquitin-mediated degradation is carried out by Crm1.
MAPK pathway, aurora B, and Histone H3 phosphorylation
As mentioned above, dysfunction of MAPK pathway has been shown to causes neuron loss and neurodegeneration in PD. In addition, it has also been demonstrated that cocaine induces the MAPK pathway and through MSK1 phosphorylates histone H3 at Ser10 (Renthal and Nestler 2008). In addition, the activation of aurora-B kinase can phosphorylate H3S10 (Latham and Dent 2007), the activity of which is affected by DNA methylation (Monier et al. 2007). It has been shown that the presence of H2AK119ub1 inhibits H3S10 phosphorylation by aurora-b kinase (Joo et al. 2007), providing a means to integrate histone ubiquitinylation with other epigenetic marks and transcriptional regulation. Aurora-b kinase is also inhibited by activation of PARP-1 providing another conduit for integrating DNA damage signaling to histone modifications (Monaco et al. 2005).
Parkinson’s disease and the sixth base
Recently, the discovery of 5-hydroxymethylcitosine (5hmC) has been added an extra layer of control to epigenetic regulation. The ten-eleven translocation family proteins (Tet1-3) catalyze the conversion of 5-mC to 5-hmC (Kriaucionis and Heintz 2009; Tahiliani et al. 2009). Although the role of 5hmC still remains to be answered it seems to play an important role in the reversion of DNA methylation and therefore reducing transcriptional repression (Thalhammer et al. 2011). It has been demonstrated that under high oxygen conditions Tet1-3 are activated by alphaketoglutarate (Chia et al. 2011). In addition, oxidative stress causes dopamine cell degeneration in PD (Jenner 2003). As a result, by considering the high amount of 5-hmC in the brain (Kriaucionis and Heintz 2009; Li and Liu 2011) and activation of TET protein family members under oxidative stress, investigation of the probable association between PD pathogenesis and 5-mC to 5-hmC conversion may shed light on some of the questions regarding the disease.
Concluding remarks and future directions
In this review, we attempted to summarize existing evidence providing potential links between epigenetic mechanisms and the pathogenesis of PD. However, since the field of PD epigenetics is largely unexplored, there are a number of key questions that remain unanswered that can guide future research: (1) does the binding of α-synuclein, or other PD risk factors, to histones or histone-modifying enzymes alter the epigenetic state of chromatin at specific genes in PD brain?; (2) is the neurotoxicity in PD the result of binding and sequestering of transcription factors, co-activators and co-repressors (e.g., CBP, p53, CtBP, and SP1 (Bossy-Wetzel et al. 2004; Hague et al. 2005; Santpere et al. 2006) leading to transcriptional dysregulation, with accumulated consequences as individuals age?; (3) Can the expression of certain transcription factors, co-activators or co-repressors even if not found to play a role in the etiology of PD provide neuroprotection?; (4) are there changes in the DNA methylation status of CpG islands and histone modifications at the promoters of PD candidate genes (SNCA, Parkin, LRRK2, UCHL1, DJ-1, and PINK) and others such as CDK5, BDNF, NURR-1, p53, MEF2D, CSN5, PITX3, and p57Kip2 in PD-affected neurons in comparison with normal cells?; (5) by treatment with MAOIs, such as tranylcypromine, that target the LSD1 family of histone demethylases, is the histone methylation pattern of key PD genes and therapeutically relevant genes altered?; (6) given that reduced levels of SKP1A, a component of BCOR complex, has been associated with sporadic PD, do other components of BCOR complex, such as FbXL10/JHDM1B and PcG proteins, contribute directly to the etiology of PD?; and (7) given that activation of PARP-1 inhibitors aurora-B kinase (Monaco et al. 2005), do changes in the level of PARP-1 associated with α-synuclein inclusions in PD change the activity of aurora-B kinase and consequently lead to alternations of the patterns of epigenetic marks in those genes, which may be influential in etiology of PD? Answering these and other questions using evolving epigenetic technologies will help elucidate the role for epigenetic mechanisms in PD.
Part of this project has been funded by Iran National Science Foundation (www.insf.org). S.J.H. is supported by Award Number R01DA028301 from the National Institute On Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute On Drug Abuse or the National Institutes of Health.