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Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 171-186

Deciphering and manipulating the epigenome for the treatment of Parkinson’s and Alzheimer’s disease

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy

Date of Submission15-Jan-2021
Date of Acceptance10-Mar-2021
Date of Web Publication02-Jun-2021

Correspondence Address:
Dr. Chidiebere Emmanuel Okechukwu
Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mgmj.mgmj_90_20

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Precision medicine intends to tailor medical practice with a focus on the individual, built on the utilization of genetic tests, the identification of biomarkers, and the development of targeted medicines, and this can be achieved by having a complex knowledge of epigenetic mechanisms. Parkinson’s disease (PD) is an age-linked neurodegenerative disease that affects majorly individuals above 65; there is a growing indication that epigenetic disruption and dysregulation in the expression of micro-ribonucleic acids (miRNAs) arise in PD. Genome-wide association studies discovered a straightforward consequence of the methylation status of α-synuclein in the pathogenesis of PD. Alzheimer’s disease (AD) is a form of neurodegenerative disease, epitomized by memory loss. The dysregulation of non-coding RNAs and epigenetic aberrations have been identified in AD. This narrative review aimed to elaborate on the potential epigenomic treatments for PD and AD. About 199 scientific articles written in English, which reported on novel epigenomic-based treatment for PD and AD, were selected for this review from the PubMed database. Full articles and relevant data were extracted. Treatments targeting DNA methylation or miRNAs appear to show promising outcomes for PD and AD. Moreover, the clustered regularly interspaced short palindromic repeats and associated protein 9 is a potential genome editing tool for deciphering and manipulating the epigenome for the treatment of PD and AD.

Keywords: Alzheimer’s disease, epigenetics, epigenomics, genome, neurodegeneration, Parkinson’s disease

How to cite this article:
Okechukwu CE. Deciphering and manipulating the epigenome for the treatment of Parkinson’s and Alzheimer’s disease. MGM J Med Sci 2021;8:171-86

How to cite this URL:
Okechukwu CE. Deciphering and manipulating the epigenome for the treatment of Parkinson’s and Alzheimer’s disease. MGM J Med Sci [serial online] 2021 [cited 2022 Oct 1];8:171-86. Available from: http://www.mgmjms.com/text.asp?2021/8/2/171/317456

  Introduction Top

Epigenetics is the study of the regulation of genes’ transcriptional capability; however, the epigenome is recognized during growth and development, but it can be altered in all the stages of life by a broad array of pharmacological agents.[1] Personalized and precision medicine intends to tailor medical practice with a focus on the individual, built on the utilization of genetic tests, the identification of biomarkers, and the development of targeted medicines, and this can be achieved by having a complex knowledge of epigenetic mechanisms.[2]

Parkinson’s disease (PD) is an age-linked neurodegenerative disease that affects majorly individuals above 65; there is growing indication that epigenetic disruptions and dysregulation in the expression of micro-ribonucleic acids (miRNAs) arise in PD. Such deviations could play a role in the primary development of PD and could serve as a biomarker for PD and can be utilized as drug targets.[3] Li et al.[4] recently observed that in the neurons of PD patients, hemispheric asymmetry in DNA methylation is larger than that in controls and implicates many PD risk genes. Epigenetic, transcriptomic, and proteomic variances between PD hemispheres are concomitant with the lateralization of PD symptoms, with aberrations being more dominant in the hemisphere corresponding to the information in the epidemiologic data. Hemispheric asymmetry and obvious lateralization in PD are linked to genes altering neurodevelopment, immune activation, and synaptic transmission. PD patients with a protracted disease path have a complex hemispheric asymmetry in neuronal epigenomes than those with a brief disease path. SNCA gene encoding alpha-synuclein is hypomethylated in PD patients; however, genome‐wide association studies revealed changes in DNA methylation on three gene variants, PARK16/1q32, GPNMB, and STX1B in PD patients.[5]

Alzheimer’s disease (AD) is a neurodegenerative disease, epitomized by memory loss and rapidly evolves into symptoms such as personality disorders and linguistic problems, resulting in loss of the capacity to carry out everyday activities and the demise of the person. Detected AD progresses over 8–10 years, but the first events of this AD could arise 20 years earlier, more than 95% of the AD cases arise sporadically in adults aged 65 years and above. The dysregulation of non-coding RNAs (ncRNAs) and epigenetic aberrations have been identified in AD. These aberrations have been observed in regions of the brain associated with learning and memory processes that are impaired in AD patients.[6] Genes precisely implicated in neurodegenerative diseases could be epigenetically altered. Diabetes, stroke, and vascular diseases are thought to be risk factors for neurodegenerative diseases, and dysregulations in cholesterol and lipid metabolism are associated with the pathogenesis of AD.[7] Several genes linked to cholesterol and lipid metabolism have methylated cytosine nucleotide and guanine nucleotide (CpG) sites in their promoters, which show abnormal deoxyribonucleic acid (DNA) methylation patterns causing the alteration of messenger RNA (mRNA) expression of genes implicated in the symptomatic phases of neurodegenerative diseases.[8],[9]

Specific polymorphisms in genes programming apolipoproteins APOB, APOC3, and APOE are linked to malfunctioning enzymatic reactions which result in an abnormal rise in the levels of low-density lipoprotein. Anomalous epigenetic regulation of these genes leads to change in expression and aberrant enzyme activities.[8] However, abnormality in lipid metabolisms is linked to vascular pathophysiology, followed by decreased oxygen and glucose supply to the brain.[9] Based on the exact location where the ischemic attack occurred, the consequent hypoxia may lead to dementia. Apolipoproteins could possess the capability to improve the clearance of amyloid-beta (Aβ), and hence they could be used as initial biomarkers of AD. Therefore, abnormal expression of these genes could alter Aβ-associated metabolism and might increase the development of Aβ plaques. An increased level of APOB mRNA and reduced APOC3 mRNA are linked to risk for AD; however, APOC3 expression could be a strong biomarker of AD.[8] The gene programming apolipoprotein E is mostly linked to hypercholesterolemia, and the APOE-ε4/ε4 haplotype is strongly associated with AD.[9] The APOE promoter is mostly hypomethylated, which normally matches with the increased gene expression. The expression of APOE is mainly regulated by miRNAs, which is a biomarker for AD.[10]

Functional indicators of neurodegeneration include decreased cell signaling and neuroinflammation, up-regulation of proinflammatory interleukins (IL-1 and IL-6), and tumor necrosis factor-alpha (TNF-α). These markers of inflammation are found to be increased in AD. TNF-α is mainly up-regulated in PD, and overexpression of IL-1 and TNF-α is associated with the hypomethylation of gene promoters.[11] TNF-α is usually hypomethylated in the dopaminergic neurons of the substantial nigra because of elevated TNF-α expression in these neurons, likened to another part of the brain in PD patients.[11] Hypomethylation in AD and PD is because of elevated homocysteine (hcy), the MTHFR gene encrypts methylenetetrahydrofolate reductase (MTHFR), which remethylates homocysteine into methionine. The polymorphisms 1298A>C (rs1801131) and 677C>T (rs1801133) in MTHFR lead to an aberrant enzyme function and the buildup of homocysteine in plasma.[12],[13] Hypermethylation of the MTHFR gene promoter is the reason for the decrease in enzymatic activity, causing an increase of hcy levels in AD patients.[12] Epigenetic description of these genes creates an avenue for the initial diagnosis of indicative phases of neurodegenerative PD and AD, which would speed up the treatment and hinder the inception of the disease. It is important to understand a patient’s pharmacogenetic status for proper precision and tailored therapy. There are inadequate data regarding the epigenetic adjustments of the biochemical reactions of drugs and carrier genes linked to PD and AD.[14],[15]

Several polymorphisms associated with the pharmacogenomic profiles are well characterized and allow the prediction of many phenotypic variations in drug response. However, there is no clear information about the effects of epigenetic variations of these genes on drug response. Numerous transporter genes are engaged in the influence of cholesterol homeostasis, and they play an important role in the development of PD and AD. Examples are the ABCA1, ABCBC1, and ABCG2, which affect AD and Aβ deposition in extracellular compartments.[16],[17],[18],[19],[20],[21] ABCA1 facilitates cholesterol and phospholipid outflow, impeding the development of Aβ deposits.[22] ABCA2, which is the extremely distributed ABC transporter in humans, may control the esterification of plasma membrane-obtained cholesterol by the regulation of sphingolipid metabolism, an aberration in the ABCA2 gene could be linked to the pathogenesis of AD.[23] The manifestation of ABC transporter genes is epigenetically controlled via the interaction with miRNAs, mainly miR-33a/b-5p, miR-106b, and miR-758-5p, controlling ABCA1 gene expression.[10] Since the past two decades, there have been tremendous efforts to create precise medicines for PD and AD. However, the intricacy of these multigenic disorders impeded the understanding of the molecular mechanisms leading to their progression, which led to inconsistent restorative mediations for PD and AD, despite widespread pharmacological treatment and lifestyle interventions.

This narrative review aimed to elaborate on the potential epigenomic treatments for PD and AD.

Bibliography search strategy

About 199 scientific articles written in English, which reported on novel epigenomic-based treatment for PD and AD, were selected for this study from the PubMed database. Full articles and relevant data were extracted. The MeSH system was used to extract relevant research studies indexed in PubMed, using the following terms: Neurodegeneration; Parkinson’s disease; Alzheimer’s disease; Epigenetic-based treatment; Epigenomics.

Manipulation of the epigenome for the treatment of PD

The epigenetic attribute of PD is typically DNA hypomethylation, which stimulates overexpression of diseased genes, for example, SNCA encrypting α-synuclein.[24] The decline in methylation is boosted through the unscrambling of DNA methyltransferases (DNMTs) by α-synuclein[25],[26] and a reduced ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM/SAH).[27] A potential therapeutic target for PD is to improve the levels of S-adenosyl-L-methionine (SAMe) which is a donor of methyl groups, through adding B vitamins and folate in the diet of PD patients.[28] Cultured cells predisposed to PD-stimulating neurotoxicity and treated with the DNMT inhibitor 5-aza-2’- deoxycytidine had reduced cell viability and worsened cell death in dopaminergic neurons, aggravating the neurotoxic damage.[29] The pathway for the pathogenesis of PD usually includes oxidative stress and mitochondrial dysfunction; hence, antioxidant-rich foods may defend against apoptosis and cease PD progression.[30]

The majority of the epigenomic-based therapies for PD are centered on the inhibition of histone deacetylase (HDAC), because of the decreased acetylation detected in cell cultures, PD-transgenic animal models, and patients with PD; the use of histone deacetylase inhibitors (HDACi) for the treatment of PD comprises sirtuin inhibitors (SIRTi) because sirtuins increase α-synuclein expression and accumulation, resulting in PD. Therefore, SIRTi could serve as a potential therapeutic target to decrease α-synuclein accumulation and aggregation.[31]

Valproic acid (VPA) is a promising HDAC for the treatment of PD; several researchers believed that VPA improved H3 acetylation and thus decreased α-synuclein-facilitated neurotoxicity and lessened inflammation in animal models exposed to PD-inducing agents.[32],[33],[34] VPA therapy augments the function of brain-derived neurotrophic factor (BDNF), which promotes the growth, survival, and synaptic plasticity of neurons.[35] VPA improves histone H3 acetylation at the promoter level of glial cell line-derived neurotrophic factor, which improves mRNA expression. VPA has the potential to prevent the apoptosis of dopaminergic neurons.[35],[36]

Sodium butyrate (NaB) is less toxic, making it a desirable medication for the treatment of PD in humans.[37],[38],[39] In animal models, NaB is effective in decreasing α-synuclein aggregation and neurotoxicity and salvaging cognitive impairments linked to PD.[40],[41],[42],[43] 4-Phenylbutyrate (4-PBA) is a form of HDACis that has neuroprotective effects.[44],[45] 4-PBA has been shown to safeguard dopaminergic neurons, perhaps through enhanced protein deglycase expression and stimulation of tyrosine hydroxylase promoter in the substantia nigra.[46] 4-PBA is effective in modifying the expression of a variety of genes connected with antioxidant enzyme chaperones, vital for cell survival.[47] Researchers should emphasize discovering epigenetic drugs for the treatment of PD [Figure 1].
Figure 1: Molecular pathway and therapeutic target for PD. Source: The Rat Genome Database (RGD) [accessed October 26, 2020]. Copyright: License CC BY 4.0. Available from: [https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?acc_id=PW:0000018#Disease]

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Manipulation of the epigenome for the treatment of AD

Numerous prospective therapies targeting epigenetic alterations in AD consist of DNMT activators and inhibitors, HDAC inhibitors, and SIRT activators.[48] Because DNA hypomethylation is linked to AD, approaches aimed to improve DNA methylation could be a favorable goal for AD treatment.[49] DNA methylation arises from folate/methionine/homocysteine metabolism, when folate, methionine, choline, and betaine enzyme’s cofactors are utilized as micronutrients.[50] Vitamin B6-dependent serine-hydroxymethyltransferase increases the transition of tetrahydrofolate (THF) into 5,10-MTHF, followed by the formation of 5-MTHF catalyzed by vitamin B2-dependent MTHFR. 5-MTHF is the methyl donor for remethylation of Hcy by cobalamin-dependent methionine synthase, yielding methionine, which is converted to SAMe by methionine adenosyltransferase.[50] SAMe is the methyl donor for DNA, proteins, neurotransmitters, hormones, and phospholipids. Donation of the methyl group promotes the synthesis of SAH, which is hydrolyzed to Hcy and adenosine by SAH hydrolase. AD is linked to increased levels of Hcy and SAH and low levels of B vitamin, folate, and SAMe, which encourages demethylation and overexpression of presenilin-1 (PSEN1) and beta-secretase-1 (BACE1). Reinstated gene expression was found after folate and B vitamins supplementation in AD mice models,[50] as well as improved cognitive functioning and slower progression of dementia.[51],[52],[53] Therefore, vitamin B, folic acid, and SAMe can be used as dietary supplements for AD treatment.[54],[55] Pathogenic genes, such as NEP, LINE-1, SORB3, and genes associated with the CREB activations pathway are hypermethylated leading to the pathogenesis of AD; treatments based on lowering DNA methylation could be appropriate for halting AD progression. Such therapies encompass the use of DNMT inhibitors which comprises nucleoside analogs, small molecules, natural products, antisense oligonucleotide (ASO) inhibitors (MG98), and miRNAs.[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66]

NaB-facilitated histone acetylation promotes long-term potentiation at Schaffer-collateral synapses in the CA1 area of the hippocampus. NaB administration during 4 weeks restored learning and memory activities in transgenic AD mice, even at a very advanced stage of pathology; they had improved formation of long-term memory.[67],[68] Protracted NaB therapy in APP/PS1-21 mice increases histone acetylation in the hippocampus, which promotes the expression of genes related to learning and memory; however, elevated doses of NaB cause a stress-like reaction which affects the epigenetic mechanism associated with learning and expressive behavior.[69],[70],[71]

4-PBA causes a rise in histone acetylation, thus enhancing the expression of genes related to synaptic plasticities, such as the ionotropic glutamate receptor 1 (GluR1), postsynaptic density protein 95 (PSD95), microtubule-associated protein 2 (MAP2), N-methyl-D-aspartate receptor subunit NR2B (NMDA-NR2B), and the synaptic-associated protein scaffold (SAP102). 4-PBA also reduces tau phosphorylation by promoting the active form of the GSK-3β, decreases Aβ accumulation, and reinstates memory function in transgenic AD mice.[72] 4-PBA restored memory and learning functions in Tg2576 AD transgenic mice by decreasing tau phosphorylation, without altering Aβ levels.[73]

VPA and NaB have been proven to reduce memory decline by increasing histone H4 acetylation.[74],[75],[76],[77],[78],[79] Trichostatin A (TSA), a class I HDACi, upsurges expression of some genes possibly through histone H4 acetylation, relating to memory consolidation, and also reinstates memory function in APP/PS1-AD transgenic mice. TSA improves induction of long-term potentiation in the hippocampus.[80],[81],[82] AD mice treated with Vorinostat (SAHA) attained increased H4K12 acetylation and reinstated expression of genes associated with learning.[83],[84] Nicotinamide is a competitive inhibitor of class III NAD+-dependent HDACs (SIRT inhibitor), which selectively decreases phosphorylated tau (at the Thr231 level), coupled with tubulin depolymerization, leading to the increase of tubulin stability. Nicotinamide has been found to reinstate cognitive deficits in AD mice.[85],[86],[87]

Entinostat (MS-275), a selective HDAC1 inhibitor, reduced neuroinflammation and amyloid buildup, followed by improvement of behavioral function in mice.[87] Mercaptoacetamide-based class II HDACi (W2) demonstrated increased memory and reduced Aβ and phosphorylated tau levels in 3xTg-AD mice.[88] Resveratrol, a natural compound found in red grapes, is a neuroprotector that inhibits Aβ aggregation, by removing oxidants and exerting anti-inflammatory activities.[89],[90] Resveratrol enhances long-term memory formation by improving SIRT1 activity and hindering Aβ-induced apoptosis; resveratrol could decrease miR-124 and miR-134 expressions, which could lead to enhancement of cyclic adenosine monophosphate response element-binding protein (CBP) levels and promotion of BDNF synthesis. These lead to increased cell viability through the stabilization of Ca2+ homeostasis, a decrease of Aβ25–35 neurotoxicity, and Rho-associated kinase 1 down-regulation.[91],[92],[93],[94],[95],[96],[97] Histone methyltransferase inhibitors (HMTis) such as SAMe induce histone acetylation to regulate gene expression or for DNA repair, SAMe enhances memory and reduces PSEN1 expression, thereby ameliorating AD symptoms.[98]

ncRNAs control the expression of genes involved in brain development and function; therefore, dysregulation of ncRNAs is linked to the pathogenesis of neurodegenerative diseases. However, the alteration and control of the expression of ncRNAs may serve as potential treatments for AD.[99] Overexpression of miR-124 and miR-195 could decrease Aβ levels by targeting BACE1; therefore, targeting of miR-323-3p would reduce inflammatory responses associated with AD.[99],[100] Phosphatase and tensin homolog (PTEN) suppression by mmiR-26a may enhance synaptic plasticity and regulate neuronal morphogenesis, and P2 × 7 receptor (P2 × 7R), an ATP-gated cation channel, promotes secretion of inflammatory factors from activated microglia. Therefore, RNA interference treatment aiming P2 × 7R decreases microglia activation and increases microglial phagocytosis of Aβ1–42.[101],[102],[103],[104] Oxidative stress due to mitochondrial dysfunction, inflammation, or metabolic stress is one of the major bases of AD pathogenesis, and this is a significant therapeutic target for the clinical management of AD [Figure 2].[105]
Figure 2: Role of mitochondria dysfunction and oxidative stress in the pathogenesis of AD. Source: Polis and Samson.[105] Copyright: License CC BY 4.0

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  Discussion Top

DNA hypomethylation and decreased histone acetylation appear to be the epigenetic characteristics of PD. However, some crucial variations in histone modifications are distinctive for PD. Aberrant miRNA and long ncRNA expressions linked to SCNA, parkin, DJ-1, and PINK1 are the most essential ncRNAs linked to PD; hypomethylation sequence in all these genes is linked to the pathogenesis of PD. This hypomethylation could be associated with the restructuring of DNMT1 by α-synuclein, which decreases DNA methylation in PD and dementia with Lewy bodies.[106],[107],[108],[109],[110] This low SAM/SAH ratio introduced in a folate-deficient diet was threatening to dopaminergic neurons in PD mouse models.[111],[112] Improved SAM/SAH ratio, which implies a higher methylation level, was associated with a better cognitive function in PD.[113]

Genome-wide association studies revealed a straightforward consequence of the methylation status of α-synuclein on the pathogenesis of PD. The supposed gene promoter, positioned in the intron 1 of SCNA gene, was hypomethylated in blood and brain samples from PD patients.[114] The hypomethylation was linked to the overexpression of α-synuclein and protein aggregation, leading to neurodegeneration.[115] This hypomethylation/overexpression is detected in substantia nigra, putamen, and cortex in reported cases of PD.[116] Higher levels of TNF-α are linked to neuroinflammation and dopaminergic cell death in PD. Consequently, further susceptibility to TNF-α regulation observed in dopaminergic neurons indicates that the gene promoter is hypomethylated.[117] Notably, overexpression of TNF-α is typically found in the cerebrospinal fluid of PD patients, as TNF-α induces apoptosis in neuronal cells.[118] There was an abnormal expression of clock genes in animal models of PD; there was reduced methylation of clock genes in PD.[119],[120],[121] DNA methylation performs an essential function in augmenting mesodiencephalic dopaminergic neuron activities, which are altered in PD.[122] Histone hypoacetylation is evidenced in PD.[123],[124],[125],[126],[127],[128] α-Synuclein-facilitated histone modifications are vital epigenetic mechanisms during the pathogenesis of PD, and the increase of nuclear α-synuclein is neurotoxic and plays a vital role in PD-related neurodegeneration, perhaps via direct binding to histones and averting H3 acetylation through interaction with SIRT2.[86],[129] HDACi therapy was able to decrease α-synuclein toxicity in neuroblastoma SH-SY5Y cells.[73] Heightened oxidative stress is a likely pathogenic factor in PD development; oxidative stress facilitates attachment of α-synuclein to the peroxisome proliferator receptor gamma coactivator-1-alpha (PGC1-α) promoter element. This binding causes histone deacetylation resulting in down-regulation of PGC1-α expression, which results in a reduction of mitochondrial biogenesis and subsequently loss of mitochondrial function.[130] Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) levels were decreased in neurons from post-mortem substantia nigra of PD patients.[131] The non-receptor tyrosine kinase C-Abl also performs a vital function in oxidative stress-induced neuronal cell death.[132] Protein kinase C-δ (PKCδ), an oxidative stress-sensitive protein, also plays a vital role in dopaminergic cell death through regulation by histone acetylation.[133],[134]

Memory decline, which is a pivotal symptom of AD, is controlled by gene expression, through DNA methylation patterns, and chromatin structure facilitated by histone modifications; consequently, histone acetylation, which has constantly been revealed to increase learning and memory, is decreased in most neurodegenerative and cognitive disorders, and treatment tactics by utilizing HDAC inhibitors appear to be effective.[135],[136]

Abnormal DNA methylation and interruption of the miRNA dogmatic circuits are connected with the accumulation of Aβ, which increases the formation of reactive oxygen species and neuronal death in AD. Elevated metabolism and prolonged existence of neurons cause the accumulation of DNA lesions; DNA repair machinery is typically inhibited by oxidative-induced post-translational modifications and degradation in AD, leading to neuronal apoptosis.[137] There is a genome-wide reduction in DNA methylation in AD.[136],[138-140] Certainly, most of the significant pathogenic genes connected with AD are hypomethylated.[141],[142],[143],[144],[145],[146],[147],[148],[149],[150],[151],[152],[153],[154],[155],[156] However, PSEN1 and the BACE1 promoter methylation and expression are also linked to folate/methionine metabolism. AD is correlated with low levels of folate and SAM.[157],[158],[159],[160]In-vitro folate deprivation and APP transgenic mice models deprived of folate and vitamins B6 and B12 led to DNA hypomethylation promoting PSEN1 and BACE1 expression, which was reinstated when deficiency of folate and vitamins was supplemented with SAM. Folate deficiency also enhances hypomethylation-mediated expression of death receptors (DR4) and DNMTs in peripheral blood lymphocytes of AD patients and cultured neuroblast cells, which could promote DNA damage and cell death.[161] Vitamin B deficiency is linked to AD-induced hypomethylation-mediated increased expression of the glycogen synthase kinase 3β gene, which is a key kinase that phosphorylates tau protein in the brain, promoting the formation of neurofibrillary tangles.[162]

PD and AD are complicated neurodegenerative disorders partly defined by genetic factors but usually develop because of the intricate interaction of genetic and environmental factors which is influenced by epigenetics.[163] Epigenomics involves the regulation of gene expression during development, maturation, and aging in physiological settings; neurodegenerative diseases and age-related cognitive impairment arise mostly due to epigenetic alterations.[164] However, epigenetic mechanisms entail the regulation of gene expression at transcriptional or post-transcriptional levels without changing the DNA sequence; these mechanisms can be altered by hormonal imbalance, reactions to medication, diet, exercise, stress, and several environmental factors. This would usually result to modifications in DNA methylation, chromatin structure, and/or ncRNA expression; this alteration results in an abnormal gene expression, which is aberrant and pathogenic, which is the hallmark of PD and AD pathogenesis.[165]

Novel epigenetic targets for the treatment of PD

Analyses of genome-wide association outcomes, expression, and epigenetic data sets of PD are a crucial step in discovering novel therapeutic targets for PD. Through novel epigenetics discovery, the risk and progression of PD can be predicted and prevented. Recently, Kia et al.[166] unraveled candidate genes (WD repeat domain 6, cluster of differentiation 38, transmembrane glycoprotein NMB, RAB29, transmembrane protein 163, zinc finger (ZF) RANBP2-type containing 3, Polycomb group ring finger 3, NIMA-related kinase 1, nucleoporin-like 2, galactosylceramidase, cathepsin B), whose change in expression, splicing, or methylation is associated with the risk of PD. The convenient method of identifying targets using eGenetics is by examining genes known to cause disease or increase risk. The LRRK2 variants are the most frequent cause of monogenic PD and one of the most known risk factors for idiopathic PD.[167] The use of ASOs to decrease the levels of active LRRK2 protein is a novel and promising therapeutic discovery, although some of the studies are still undergoing clinical trials.[168] ASOs target precisely and persistently decrease LRRK2 kinase activity by editing out the parts of the mRNA known to contain disease-associated variants.[168] The main clinical goal of ASOs is to reduce LRRK2 kinase activity and lessen LRRK2-associated neuronal dysfunction in PD.[168] PD patients with glucocerebrosidase gene (GBA) mutations seem to have an earlier age at onset, more rapid disease progression, and a larger burden of non-motor symptoms.[169] There are two familiar GBA variants (p.E326K and p.T369M) related to PD risk that may adjust glucocerebrosidase (GCase) activity to a lesser level.[170] Current clinical trials are targeting improving GCase substrate reduction. Ambroxol therapy increased β-GCase enzyme activity and reduced α-synuclein levels in patients with PD with and without GBA gene mutations.[171] lncRNA nuclear-enriched assembly transcript 1 (NEAT1) has been reported to be highly expressed in PD. However, NEAT1 knockdown suppressed PD progression in mouse models, through regulating the miR-212-3p/ axis inhibition protein 1 pathway, suggesting that NEAT1 might be a therapeutic target for neuroprotection in patients with PD.[172]

Several epigenetic therapeutic targets (synaptic vesicle glycoprotein 2C, α-synuclein, c-Abl, G protein-coupled receptor 109 A, and transcription factors) have been identified lately, and they can be modified for the treatment of PD.[173] However, more clinical trials are needed to substantiate the efficiency of these therapeutic targets in PD.

Novel epigenetic targets for the treatment of AD

Presently, there is no effective therapy to treat and prevent the progression of AD, which implies the need to develop novel therapeutic targets and agents for AD.[174] Sirtuins, particularly SIRT3, a mitochondrial deacetylase, are NAD-dependent HDACs involved in aging and longevity.[174] Several scientific reports suggest that SIRT3 dysfunction is robustly linked with the pathophysiology of AD.[174] Therefore, therapeutic modulation of SIRT3 activity may be a novel discovery to treat AD. Moreover, the use of SIRT3 activators (e.g., metformin, silybin, polydatin, pyrroloquinoline, and 7-hydroxy-3-(4-methoxyphenyl)-4-methyl coumarin) may be potential therapeutic approaches in the treatment of AD.[174]

Intricacy in AD pathology impedes the development of restorative approaches.[175] For effective countering of AD, these three neuropathological processes must be reversed: (i) the development of Aβ plaques extracellular matrix by aggregation of insoluble Aβ oligomers; (ii) the development of neurofibrillary tangles by hyperphosphorylation of tau proteins; and (iii) neuronal loss as a result of the preceding neuropathological mechanisms.[175] Hence, several treatment strategies failed in enhancing cognitive function in AD patients because most drugs targeted specific neuropathological processes without reversing other neuropathological mechanisms.[175] Hence, a multitargeted approach is needed to concurrently target distinct pathways and cure AD.[175] Additional, potential therapies for AD consist of therapeutic agents reliant on blocking mammalian targets of rapamycin and glycogen synthase kinase-3b and decreasing neuroinflammation by lowering tau phosphorylation and improving Aβ clearance.[175] Moreover, recent advances in nanomedicine present prospects for the delivery of active therapeutic agents to actual targets. The essential nanoformulations being examined against AD include polymeric nanoparticles (NPs), inorganic NPs, and lipid-based NPs.[175] Nanodrug transport techniques are promising innovations, targeting numerous therapeutic pathways via easing drug molecules’ entry across the central nervous system and enhancing their bioavailability.[175] However, epigenetic de-repression of neuronal Nrf2 facilitates the response of Nrf2 activators to push α-synuclein clearance; therefore, activation of neuronal Nrf2 expression using gRNA-targeted dCas9-based transcriptional activation complexes is enough to trigger Nrf2-dependent α-synuclein clearance.[176] Hence, targeting reversal of the developmental processes of Nrf2 in forebrain neurons might alter neurodegenerative disease pathways by enhancing proteostasis.[176]

Inhibiting miR-331-3p and miR-9-5p prevented AD progression by promoting the autophagic clearance of Aβ in mice.[177]Cognition-enhancing agents (J147 and CMS121) show promising signs in improving brain functioning in mice.[178]

Preventive approaches regarding the impact of environmental and lifestyle factors in the etiology of PD and AD

Exposure to industrial chemicals, comprising pesticides, solvents, and heavy metals, has been discovered to increase the risk for PD.[179] Impacts of these environmental exposures well experiment in animal models. Some lifestyle behaviors have been linked with a decreased incidence of PD, including smoking, caffeine and tea intake, use of non-steroidal anti-inflammatory drugs, and exercise.[179] Lifestyle modifications such as dietary changes have been considered as a preventive approach for AD and PD.[179] Such dietary modifications have been studied in fly models with LRRK2 (p.G2019S), and they have indicated a protective effect.[179] Normal consumption of dietary amino acids is vital for dopamine neuron survival and motor function. Environmental toxins linked with the pathogenesis of PD mostly consist of inhibitors of mitochondrial complexes and/or inducers of cellular reactive oxygen species.[179] Dietary lipids are significant risk factors for the development of AD.[180] However, fish consumption was discovered to be a significant risk reduction approach for AD.[180] Moreover, a high-fat diet can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are involved in oxidative stress possibly leading to the neuroinflammation and damage discovered in AD. The dietary risk factors for AD are mainly high cholesterol and fat diet; on the contrary, the risk reduction factors are diets rich in whole grain cereals and vegetables.[180] Clinical studies regarding nutritional preventative strategies, such as probiotic use and dietary interventions for AD, are still on trial.[181]In-vivo animal experiments showed that exposure to environmental pollutants including arsenic, burning coal, gasoline, fine particulate matter (PM2.5), cadmium, asbestos, and aniline produces aberrations in genes vital in regulating DNA methylation patterns (Dnmt1, Dnmt3a, MeCP2, Gadd45b, and Hdac1), at various gene loci in the medial prefrontal cortex of the brain, thus altering and modifying the network of genes involved in mental activities.[182],[183] Individuals who work in hydrocarbon industries are more exposed to environmental toxins. However, controlling and minimizing the exposures to environmental pollutions, adopting a healthy diet plan (e.g., Mediterranean diet), and regular physical activity routine may reduce the risk of PD and AD.

Novel genomic techniques for deciphering and manipulating the epigenome for the treatment of PD and AD

The capability to precisely edit the epigenome possesses the potential of improving knowledge of how epigenetic modifications function, enabling manipulation of cell phenotype for therapeutic purposes.[184] Genome engineering techniques use extremely precise DNA-targeting tools to specifically set epigenetic changes in a locus-specific approach.[185] Genetic methods that influence genome structure and/or gene expression simplify mirroring of the distress of distinct elements of the epigenome, thus providing important understandings of the target genes.[185] The advancement of genome-modifying tools that can competently and precisely target specific DNA sequences has formed a multipurpose variety of targeted sites, including mostly ZFs, transcription activator-like effectors, and the famous clustered regularly interspaced short palindromic repeats and associated protein 9 (CRISPR-Cas9) system [Figure 3].[184],[185],[186] These techniques differ in approach, application, and efficacy, and they are all connected to epigenome editing tools and can successfully and precisely carry engineered proteins that have a functional epigenetic altering moiety to their targets.[185],[187] Due to the simplicity of use and effectiveness of the CRISPR system and the associated “dead” nuclease-inactive Cas9, evolving epigenome editing tools are concentrating mainly on the CRISPR technique.[184],[185],[186],[187] The CRISPR-Cas9 is developing as a potent genomic tool to fix abnormal genetic alterations and is currently commonly used in the study of AD. CRISPR-Cas9 has been proven to be a precision-based tool for editing genes, and it shows enormous potential in the correction of the undesirable mutations in AD-linked genes such as APP, PSEN1, and PSEN2.[188] Therefore, it has opened a new door for the development of empirical AD models, diagnostic approaches, and therapeutic lines in studying the complexity of neurodegenerative diseases, ranging from different cell types (in vitro) to animals (in vivo).[189],[190],[191] The CRISPR-Cas9 technique shed light on the critical elements behind the PD pathogenesis.[192] Moreover, the CRISPR-Cas12a possesses the ability to target T-rich motifs—without trans-activating crRNA—and induction of a staggered double-strand break as well as the potential for both RNA processing and DNA nuclease activity.[192] The CRISPR-Cas9 combined with repair template-mediated homology targeted repair to create the LRRK2 G2019S mutation, and curtailing of the LRRK2 kinase domain, into marmoset embryonic and induced pluripotent stem cells.[193] The CRISPR-Cas9 is a sequence of a single-guide RNA (sgRNA) for detecting the target location and a Cas9 protein as nuclease for cutting DNA.[194] CRISPR-Cas9 has numerous forms: one form is wild-type (wt)-CRISPR-Cas9 and Cas9 nickase (nCas9) that can work beyond the editing of the genome; the Wt-CRISPR-Cas9 system comprises a nuclease called Cas9 which produces a DNA double-strand break (DSB) and an sgRNA.[194] HNH and RuvC nucleases are the catalytic domains of wt-CRISPR-Cas9, and these two elements are liable for inducing double-strand breaks in the target gene.[194] Via reprogramming and artificial inactivation, either of these two parts, wt-Cas9, turns into nCas9 and leads to single-strand breaks; pair of nCas9 can be applied to generate two nicks to lessen off-target cleavage. The duplex RNA used in the CRISPR-Cas9 system is a truncated one and linked together to form a stem-loop structure to affix to the target site. Through leading sgRNA that comprises CRISPR-derived RNA and trans-activating CRISPR RNA (tracrRNA) that form the two-RNA structure of sgRNA, Cas9 can precisely knock-out/in marked target genes.[194] The sgRNA has a plain and straight structure that is simply created. The Cas9-based structure can simply be linked to virtually any position of the genome that the sgRNA is selected matching.[194] However, the CRISPR-Cas9 system precisely targets every 20 bp genomic DNA sequence that is followed by the 5′-NGG-3′ protospacer adjacent motif (PAM) sequence, and the Cas9 nuclease cleaves 3 bp upstream from the PAM sequence inside the target gene and created DSB in non-homologous end-joining or homologous recombination forms.[194] The precision and effectiveness of the CRISPR-Cas9 system are mostly determined by the PAM sequence and the 17–20 nucleotide sequence at the 5′ end of gRNAs. The genetic modifications carried out via the CRISPR-Cas9 are constrained to the particular target site and are away from the off-target sequence, which expresses the specificity of the CRISPR-Cas9 system.[194] If both HNH and RuvC domains are turned off, wt-CRISPR/Cas9 system is switched to dead Cas9 (dCas9), which then can perform as a DNA binding tool with high specificity and sensitivity and without endonuclease activity.[194] This method can be coupled with multiple modifiers like epigenetic effectors for the modulation of gene expression. Moreover, the single-strand RNA can be targeted by creating new Cas/sgRNA to identify and cleavage target ssRNA. These innovative tools dubbed RNA-targeting Cas9, and artificial inactivation of Cas9 into dCas9 in this novel platform leads to the formation of dead RNA-targeting Cas9 that affects RNA function such as splicing, translation, and RNA editing by its combined effectors.[194] Based on the progression in target site detection techniques in the CRISPR-Cas9 platform, and by detecting modified Cas9 enzymes, the risk of off-target activities in the CRISPR-Cas9 system has reduced. Moreover, the CRISPR-Cas9 system can identify numerous target locations easily via the use of multiple gRNAs.[194]
Figure 3: Applications of genome editing techniques (ZFNs, TALENs, and CRISPR-Cas9) in the epigenetic therapy for PD and AD. Source: Yang et al.[186] Copyright: License CC BY 4.0

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Additionally, the application of CRISPR-Cas9 has been utilized to analyze neuroinflammatory pathways involved in the PD pathogenesis, such as the PKCδ signaling pathway, and the roles of new protective pathways, such as Prokineticin-2 signaling.[195] In contrast, the CRISPR-Cas9 can be utilized to irrevocably deactivate or repair defective genes in AD. However, the major challenge is the safety and effectiveness of the delivery system which poses an obstacle in the translation of the CRISPR-Cas9 technique from bench to bedside.[196] Viral vectors are effective in CRISPR-Cas9 delivery, but they may create lethal side effects and immune responses in humans; moreover, other possible non-viral vectors that can be utilized for genome editing in AD are NPs, nanoclews, and microvesicles.[196]

  Future perspectives Top

DNA methylation, a process by which methyl groups are incorporated into cytosine molecules by DNMTs, is a hallmark of epigenetics; methylation normally occurs at CpG areas defined as regions where the CG content is greater than 60%. Gene promoters with rich content of CpG areas are most likely to be hypermethylated as approximately 70% of the CpG dinucleotides within the human genome are methylated. Significant DNA methylation changes exist in PD; however, the cause of these methylation changes is not yet known. Therefore, more genome-wide brain DNA methylation analysis regarding epigenetic reprogramming in PD is needed to unravel more information that will optimize potential epigenomic-based treatments for PD.[197] Regarding AD, post-translational histone modifications and chromatin structure undergo significant alterations with age. Histone H3 and H4 methylation declined progressively with age; an age-related decrease of histone acetylation leads to a close chromatin conformation and subsequent lack of accessibility for DNA repairing enzymes and other regulatory factors, which led to an impaired synaptic plasticity and memory formation due to the transcriptional repression of crucial genes.[198] Therefore, increasing histone acetylation could be a fascinating therapeutic target for AD. HDACis could also be effective in the treatment of PD and AD; hence, further studies are needed to identify the best isoform or isoforms of HDACis that could exert significant therapeutic effects without being neurotoxic.[199]

  Conclusion Top

There is an urgent need to develop new therapeutic strategies and innovative drugs that can delay the onset and progression of PD and AD, improve the quality of life of patients with PD and AD, and minimize their cost of treatment and hospitalization. Nevertheless, these can be achieved through the manipulation of the epigenome by targeting epigenetic modifications using novel pharmaceutical agents. Treatments targeting DNA methylation or miRNAs seem to show promising outcomes for PD and AD. Moreover, the CRISPR-Cas9 is a potential genome editing tool for deciphering and manipulating the epigenome for the treatment of PD and AD.

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Conflicts of interest

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