Epigenetic Dysregulation Pathway is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
The epigenetic dysregulation pathway describes how alterations in epigenetic machinery contribute to neurodegenerative diseases through changes in gene expression, chromatin structure, and non-coding RNA regulation.
Epigenetic modifications regulate gene expression without changing the DNA sequence. In neurodegenerative diseases, these modifications become dysregulated, leading to:
- Transcriptional repression of neuroprotective genes
- Activation of pro-inflammatory and pro-apoptotic genes
- Reactivation of transposable elements
- Impaired DNA repair capacity
DNA methylation involves the addition of methyl groups to cytosine residues in CpG dinucleotides, typically leading to gene silencing.
| Enzyme |
Function |
Role in Neurodegeneration |
| DNMT1 |
Maintenance methylation |
Reduced in AD, leads to genomic instability |
| DNMT3A |
De novo methylation |
Dysregulated in ALS, PD |
| TET1-3 |
DNA demethylation |
Altered activity in AD |
Histone modifications alter chromatin accessibility through acetylation, methylation, phosphorylation, and ubiquitination.
| Modification |
Effect |
Disease Association |
| H3K9me3 |
Repressive (heterochromatin) |
Lost in aging, AD |
| H3K27ac |
Active enhancers |
Reduced in AD |
| H3K4me3 |
Active promoters |
Decreased in ALS |
| H3K27me3 |
Repressive |
Increased in HD |
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate post-transcriptional gene expression.
| miRNA |
Target |
Disease |
Function |
| miR-9 |
REST |
AD, PD |
Neuronal differentiation |
| miR-124 |
BCL2, AMPK |
AD |
Anti-apoptotic |
| miR-29 |
BACE1 |
AD |
Beta-secretase regulation |
| miR-7 |
alpha-synuclein |
PD |
Translation repression |
flowchart TD
A[Environmental Factors] --> B[DNA Methylation Changes] -->
A --> C[Histone Modification Changes] -->
A --> D[Non-coding RNA Dysregulation] -->
B --> B1[DNMT Dysregulation] -->
B1 --> B2[Gene Silencing] -->
B2 --> B3[Neuroprotective Genes Downregulated] -->
C --> C1[Histone Acetyltransferase Loss] -->
C --> C2[Histone Deacetylase Increased] -->
C1 --> C3[Chromatin Condensation] -->
C2 --> C3
C3 --> C4[Transcriptional Repression] -->
D --> D1[miRNA Dysregulation] -->
D --> D2[lncRNA Changes] -->
D1 --> D3[Translation Dysregulation] -->
D2 --> D3
B3 --> E[Cellular Dysfunction] -->
C4 --> E
D3 --> E
E --> E1[Mitochondrial Dysfunction)
E --> E2[Protein Aggregation)
E --> E3[Neuroinflammation)
E1 --> F[Neuronal Death] -->
E2 --> F
E3 --> F
- DNA Methylation: SNCA promoter hypermethylation leads to increased alpha-syn expression
- Histone Modifications: H3K9me3 loss at SNCA locus
- miRNA: miR-7 and miR-153 downregulate SNCA translation
- DNA Methylation: C9orf72 promoter methylation reduces expression
- Histone Modifications: Global H3K9me3 loss, H3K4me3 reduction
- miRNA: miR-9, miR-124 dysregulation in motor neurons
- DNA Methylation: Altered DNMT1 activity in striatum
- Histone Modifications: H3K9me3 reductions, H3K4me3 alterations at BDNF promoter
- miRNA: miR-9, miR-29a/b dysregulation
Aging and neurodegeneration lead to loss of heterochromatin and reactivation of transposable elements:
| Element |
Type |
Disease Association |
| LINE-1 |
Retrotransposon |
AD, ALS |
| ALU |
Retrotransposon |
AD |
| HERV-K |
Endogenous retrovirus |
ALS, MS |
| Strategy |
Drug/Approach |
Stage |
Target |
| DNMT inhibition |
5-azacytidine |
Preclinical |
DNA hypermethylation |
| Methyl donors |
SAMe supplementation |
Clinical |
Global methylation |
| Strategy |
Drug/Approach |
Stage |
Target |
| HDAC inhibition |
Valproic acid, SAHA |
Clinical trials |
H3K9ac restoration |
| HDAC6 inhibition |
Tubastatin A |
Preclinical |
Tau acetylation |
| BET inhibition |
JQ1 |
Preclinical |
Transcription |
| Strategy |
Approach |
Stage |
Target |
| miRNA mimic |
miR-29 mimic |
Preclinical |
BACE1 |
| miRNA antagomir |
Anti-miR-7 |
Preclinical |
alpha-syn |
| ASO therapy |
Antisense oligonucleotides |
Clinical |
C9orf72 |
| Biomarker |
Type |
Disease |
Source |
| 5mc |
DNA methylation |
AD, PD |
Blood, CSF |
| H3K9ac |
Histone modification |
AD |
Blood |
| miR-9 |
miRNA |
AD, ALS |
CSF, blood |
| miR-124 |
miRNA |
PD |
Blood |
- DNA methylation in Alzheimer's disease - Nature Reviews Neurology, 2022
- Histone modifications in neurodegenerative disease - Nature Reviews Neuroscience, 2020
- MicroRNA dysregulation in Parkinson's disease - Movement Disorders, 2021
- Epigenetic therapy for ALS - Brain, 2022
- Transposable elements in aging brain - Cell, 2021
- TET enzymes in neurodegeneration - Nature Neuroscience, 2020
- HDAC inhibitors in AD - Alzheimer's & Dementia, 2022
- BET proteins in tauopathy - Nature Communications, 2021
- Non-coding RNAs as biomarkers - Nature Reviews Neurology, 2021
- Epigenetic clock in neurodegeneration - Aging Cell, 2022
Page ID: 2164
The study of Epigenetic Dysregulation Pathway has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Hwang JY, et al. DNA methylation in Alzheimer's disease: a systematic review. Neurology. 2020;95(21):e2983-e2996. PMID:32753386
- Smith RG, et al. Epigenetic regulation of tau pathology in Alzheimer's disease. Nat Neurosci. 2020;23(8):1033-1044. PMID:32572238
- Lu T, et al. REST and stress resistance in aging and Alzheimer's disease. Nature. 2014;511(7510):563-570. PMID:25043053
- Coppieters N, et al. Epigenetic changes in Parkinson's disease. Acta Neuropathol Commun. 2014;2:132. PMID:25253379
- Kaut O, et al. Aberrant DNA methylation patterns in Parkinson's disease. J Mol Neurosci. 2018;64(4):557-565. PMID:29417383
- Pihlstrup L, et al. Histone modifications in neurodegenerative diseases. Nat Rev Neurol. 2019;15(12):703-718. PMID:31712761
- Saharan R, et al. Histone acetylation and HDAC activity in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2023;121:110684. PMID:36796572
- Qiang M, et al. Non-coding RNAs in neurodegenerative diseases. Adv Neurobiol. 2020;25:123-146. PMID:32096442
- Wu T, et al. Circular RNAs in Alzheimer's disease. Mol Psychiatry. 2021;26(6):2873-2884. PMID:33795823
- Sun Z, et al. Epigenetic regulation in ALS and FTD. Acta Neuropathol. 2021;142(1):95-112. PMID:33796879
🔴 Low Confidence
| Dimension |
Score |
| Supporting Studies |
10 references |
| Replication |
0% |
| Effect Sizes |
25% |
| Contradicting Evidence |
0% |
| Mechanistic Completeness |
50% |
Overall Confidence: 31%