DNA Methylation: A Promising Approach in Management of Alzheimer’s Disease and Other Neurodegenerative Disorders
Abstract
:Simple Summary
Abstract
1. Introduction
2. History and Development of DNA Methylation
3. Methylation Detection Method
4. DNA Methylation in Premature and Mature Brain
5. Role of DNA Methylation in Neurological Disorders
5.1. Alzheimer’s Disease
5.2. Parkinson Disease
5.3. Huntington Disease
5.4. Amyotrophic Lateral Sclerosis
6. Targeting DNA Methylation in Management of AD and Other Neurodegenerative Diseases
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Disease | Sample | Methylation (Hyper/Hypo) | Experimental Method | Gene | Ref. |
---|---|---|---|---|---|
AD | Blood | Hypermethylation | Bisulphite sequencing PCR and methylation-specific PCR are used | SIRT1 | [53] |
AD | Dorsolateral prefrontal cortex tissue | Differently methylated | CpG sites generated using a bead assay | SORL1, ABCA7, HLA-DRB5, SLC24A4, BIN1. | [54] |
AD | Hippocampus | Hypomethylation | Bisulfite cloning sequencing of CpG sites in two promoter regions Prom1 and Prom2 | CREB-regulated transcription factor 1 | [55] |
AD | Blood | Hypermethylation | Bisulfite treated DNA was analyzed by melting curve analysis-methylation assay | UQCRC1 | [56] |
AD | Hippocampus | Hypermethylation | Bisulfite cloning sequencing and further measured by 5-hydroxymethycytosine (5hmC) | TREM2 | [57] |
AD | Blood | Hypermethylation | Dual-luciferase assays | OPRM1, OPRL1 | [58] |
AD | Blood | Hypomethylation | Quantitative bisulfite-PCR pyrosequencing | PICALM | [59] |
AD | Brain | Hypermethylation | Bisulfite pro-sequencing | ANK1 gene | [60] |
AD | Hippocampus | Hypermethylation | RT-qPCR | PLD3 gene | [61] |
PD | Postmortem human brain samples (frontal cortex) | Hypermethylation | Illumina Infinium array | MRI1, TMEM9 | [62] |
PD | Postmortem human brain samples (frontal cortex) | Hypomethylation | Illumina Infinium array | GSST1, TUBA3E, KCNH1 | [62] |
PD | Brain tissue | Hypomethylation | Fluorescence-activated nuclei sorting and bisulfite pro-sequencing | CpGs located in SNCA intron 1 | [63] |
PD | Blood | Differently methylated | Cross-sectional analysis of blood methylation | SRSF7, ADNP, GDNF, SYN3, CPLX1, SNCA, TREM2. | [64] |
PD | Blood and saliva | Altered methylation | Illumina Infinium array | ABCB9, C1orf200, AZU1, LARS2, PARK2, LRRK2, APC, AXIN1 | [65] |
PD | Brain | Differently methylated | Genome wide screening and RNA sequencing | ARFGAP1, DUSP22 promoter, SNCA | [66] |
PD | Leukocytes | Hypomethylation | Methylation-specific PCR | NPAS2 | [67] |
PD | Brain | Hypermethylation | Bisulfite sequencing and micro array gene expression analysis | PGC1-α | [68] |
PD | Brain | Hypomethylation | Genome wide methylation | CYP2E1 | [69] |
PD | Blood | Hypomethylation | - | NOS2 | [70] |
PD | Leukocytes, Brain | Hypermethylation | Bisulfite pyrosequencing and MAPT promoter methylation assay | MAPT | [71] |
PD | Brain | Hypermethylation | Illumina Infinium array | FANCC/TNKS2 | [72] |
HD | Striatal cells carrying polyglutamine-expanded HTT (STHdhQ111/Q111) and wild-type cells (STHdhQ7/Q7) | Altered DNA methylation | mRNA-Seq, ChIP-Seq assay and Motif Scanning | Htt | [73] |
HD | Prefrontal cortex | Differently methylated | Fluorescence-based nuclei sorting (FACS)-ChIP-seq | HES4 | [74] |
HD | Putamen of HD patients and striatum of mice | Differently methylated | Bisulfite sequencing and TaqMan PCR | ADORA2A | [75] |
HD | Blood | Differently methylated | Microarray methylation | CLDN16, NXT2, DDC. | [76] |
HD | Blood | Differently methylated | mRNA-Seq, ChIP-Seq assay and motif scanning | FBXL5, S100P, PRDX1, COPS7B, SP1, SEC24C, PDIA6, USP5, GRAP, POP5, WRB, PCSK7. | [77] |
ALS | Postmortem spinal cord tissue | Hypomethylation | Bisulfite pyrosequencing, genome-wide expression profiling, and RT-PCR | MLC1, CRB1, CTNND2, FURIN, SLC31A1, CMTM3, STAT5A, SRGAP1, LPXN, PLD4, OBFC2A, TXNIP, PSAP, SLC35E1, RBM38, CLEC4A, HMHA1, PLSCR1, AXL, PHYHD1. | [78] |
ALS | Postmortem spinal cord tissue | Hypermethylation | Bisulfite pyrosequencing, genome wide expression profiling, and RT-PCR | LUM, SLC13A4, GJB2, TYRP1, CLDN19, LINGO2, PLEKHA4, NNAT, TSPAN18, PLCB4, TMEM139, PNMAL1, DMBT1, TNFSF10, NNAT, PCP4, MAB21L2, PEG10, TMEM139, KCNJ12, FGF18. | [78] |
Methylation of DNA | Gene/Target/Pathway Involved | Effect | Model | Experimental Method | Outcomes | Ref. |
---|---|---|---|---|---|---|
5-mC | B3GALT4, ZADH2 | Decrease | AD and healthy patients | Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test Part B (TMT-B), INNOTEST assays, and Triplex assay | Hypomethylation of B3GALT4, ZADH2 associated with the level of AB and tau in CSF | [139] |
5-mC | HOXA3, GSTP1, CXXC1-3, BIN1 | Increase | AD and healthy patients | Laser-assisted microdissection and Infinium DNA Methylation 450K analysis | 504 DMCs and 237 DMRs were identified and increased in the 5mC pyramidal layer, which is associated with oxidative stress | [140] |
5-mC | KIAA056 | Decrease | NFT pathology stages I-IV | Bisulfite sequencing and Infinium Human Methylation 450 BeadChip | Downregulation of 5mC in KIAA056 and in NFT pathology cases | [141] |
5-mC | ANKRD30B, ANK1, Cell adhesion | Increase | AD and neurotypical patients | Genome-wide DNA methylation, mRNA expression profiling, functional enrichment analysis, and differential methylation of genes | 856 DMCs were identified along with a correlation between 5-mC and gene expression | [142] |
5-mC | WNT5B, ANK1, ARD5B | Increase and decrease | AD patients | Illumina Infinium Human Methylation 450K microarray | Increased 5-mC level in WNT5B, ANK1, and decreased in ARD5Bz | [143] |
5-mC | Amyloid neuropathy and neurogenesis | Decrease | AD and healthy patients | RNA sequencing, aging analysis, gene annotation, and enrichment analysis | Identification of 1224 DMRs, enhancement in the DCSAML1 gene which targets BACE1 | [144] |
5-mC | - | Decrease | AD and healthy patients | Immunohistochemistry | Downregulation of 5-mC and negative correlation between 5mC and amyloid plaque level | [145] |
5-mC | - | Increase | AD patients and preclinical samples | Immunohistochemistry | Upregulation of 5-mC and hippocampus gyrus in both clinical and preclinical cases | [146] |
5-mC | - | Increase | Early and late-onset AD patients | Immunohistochemistry | Upregulation of 5mC in middle frontal gyrus and middle temporal gyrus in AD patients and shows a positive correlation with AD biomarkers | [147] |
5-mC | AS3MT, WTI, TBX15 | Decrease | AD with psychosis and without psychosis patients | Immunohistochemistry | Decrease level of AS3MT, WTI, TBX15 gene associated with AD patients | [148] |
5-mC | - | Decrease | Early and late AD patients | Immunohistochemistry | Genetic dysregulation may be occurring in astrocytes and NF-positive pyramidal neurons in AD | [149] |
IL-1β Promoters | IL-1β | Decrease | BALB/c mice (3–4- and 18–20-month-old) | LPS-induced neuroinflammation and Quantitative PCR (qPCR) | Microglial transferred to M1 phenotype which causes neuroinflammation and neuronal cell damages | [150] |
SNCA Promoters | SNCA | Decrease | Healthy and PD patients | qPCR | Aggregation of a-syn, neuronal damage of DA, and neuroinflammation is triggered by activating glial cells | [151] |
PGC-1α Promoters | PGC-1α | Increase | Human brain of PD and healthy patients | Bisulfite sequencing, Microarray gene expression analysis, ELISA analysis | Up-regulation of neuroinflammation, ER stress, epigenetic modification, and ROS production | [152] |
TNF-α Promoters | TNF-alpha | Decrease | PD and healthy patients | Bisulfite PCR and sequencing | SNpc cells could underlie the increased susceptibility of dopaminergic neurons to TNF-alpha-mediated inflammatory reactions. | [153] |
NOS2 Promoters | NOS2 | Decrease | PD and healthy patients | Qiagen’s Assay | Down-regulation of NO production to deactivate the microglial | [154] |
Neurodegenerative Disease | Drug | Class of Drug | Inference | Reference |
---|---|---|---|---|
AD | Epigallocatechin gallate, epigallocatechin 3-gallate, tea catechin, tea vigo, catechin deriv., | DNMT inhibitors | Improve memory, prevent cell death in Aβ-treated neurons, Aβ aggregation. | [174] |
AD | Vitamin B6, folate, Folacin; Pteroylglutamic acid | SAMe methyl donors | Attenuate homocystine level | [174] |
PD | 5-Aza-2′-Deoxycytidine | DNMTs inhibitor | Upregulate tyrosine hydroxylase, dopamine production, and alpha-synuclein expression | [175] |
HD | decitabine and FdCyd | DNMTs inhibitors | Restore expression of Bndf | [176] |
ALS | RG108 | DNMTs inhibitors | Block DNA methylation accumulation in motor neurons | [177] |
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Kaur, G.; Rathod, S.S.S.; Ghoneim, M.M.; Alshehri, S.; Ahmad, J.; Mishra, A.; Alhakamy, N.A. DNA Methylation: A Promising Approach in Management of Alzheimer’s Disease and Other Neurodegenerative Disorders. Biology 2022, 11, 90. https://doi.org/10.3390/biology11010090
Kaur G, Rathod SSS, Ghoneim MM, Alshehri S, Ahmad J, Mishra A, Alhakamy NA. DNA Methylation: A Promising Approach in Management of Alzheimer’s Disease and Other Neurodegenerative Disorders. Biology. 2022; 11(1):90. https://doi.org/10.3390/biology11010090
Chicago/Turabian StyleKaur, Gagandeep, Suraj Singh S. Rathod, Mohammed M. Ghoneim, Sultan Alshehri, Javed Ahmad, Awanish Mishra, and Nabil A. Alhakamy. 2022. "DNA Methylation: A Promising Approach in Management of Alzheimer’s Disease and Other Neurodegenerative Disorders" Biology 11, no. 1: 90. https://doi.org/10.3390/biology11010090