Epigenetic regulation refers to heritable and reversible control of gene expression without changing the underlying DNA sequence. Major mechanisms include DNA methylation (5-methylcytosine, 5-hydroxymethylcytosine), histone modifications (acetylation, methylation, phosphorylation, ubiquitination), chromatin remodeling complexes, and regulatory non-coding RNAs (miRNAs, siRNAs, lncRNAs, circRNAs).[1][2] In neurodegenerative diseases, epigenetic disruption alters neuronal identity programs, stress responses, inflammatory tone, proteostasis, and vulnerability to toxic protein accumulation.[3][4]
DNA methylation involves the addition of a methyl group to cytosine residues in CpG dinucleotides, typically resulting in gene silencing. 5-methylcytosine (5mC) can be oxidized to 5-hydroxymethylcytosine (5hmC), which is enriched in neurons and associated with active gene expression.[5]
Key enzymes:
Alzheimer's disease:
Parkinson's disease:
ALS/FTD:
Histones undergo post-translational modifications that alter chromatin structure and gene expression.
| Modification | Function | Key Enzymes |
|---|---|---|
| Acetylation | Open chromatin, active transcription | HATs (p300/CBP, PCAF), HDACs (class I/II/III) |
| Methylation | Activation or repression (site-dependent) | HMTs (SETD2, PRDM2), KDMs |
| Phosphorylation | DNA damage response, activation | kinases, phosphatases |
| Ubiquitination | Degradation, transcription regulation | E3 ligases, deubiquitinases |
| SUMOylation | Repression, protein stability | SUMO E1/E2/E3, SENPs |
Alzheimer's disease:
Parkinson's disease:
ALS:
ATP-dependent chromatin remodelers alter nucleosome positioning to regulate gene expression.
Key complexes:
Neurodegeneration relevance:
miRNAs are ~22 nucleotide RNAs that repress translation or promote mRNA degradation.
Key miRNAs in neurodegeneration:
lncRNAs (>200 nt) regulate gene expression through various mechanisms.
Key lncRNAs:
circRNAs are stable circular RNAs derived from back-splicing.
The amyloid precursor protein (APP) gene promoter is subject to epigenetic regulation:
Tau protein (MAPT) expression is epigenetically regulated:
Epigenetic age acceleration associates with:
The SNCA gene encoding α-synuclein is regulated by:
LRRK2 (leucine-rich repeat kinase 2) regulatory regions show:
Epigenetic factors in dopaminergic neuron loss:
The most common genetic cause of ALS/FTD involves:
TDP-43 (TARDBP) regulates:
| Drug | Class | Status | Evidence |
|---|---|---|---|
| Valproic acid | HDAC I/IIa inhibitor | Approved (bipolar) | Preclinical AD/PD |
| Vorinostat | HDAC I/II/III inhibitor | Approved (cancer) | Phase trials AD |
| Sodium butyrate | HDAC I/II inhibitor | Preclinical | Memory enhancement |
| Entinostat (MS-275) | Class I selective | Phase trials | Preclinical AD |
| RG108 | DNMT inhibitor | Preclinical | Demethylation |
| Drug | Status | Evidence |
|---|---|---|
| Azacitidine | Approved (cancer) | Preclinical |
| Decitabine | Approved (cancer) | Preclinical |
| RG108 | Preclinical | Demethylation |
DNA methylation patterns are altered in neurodegenerative diseases
Histone modification patterns in neurodegeneration- Histone acetylation: Generally reduced in disease
microRNAs and other ncRNAs in neurodegeneration- miR-7: Alpha-synuclein targeting in PD
| Drug | Target | Disease | Status |
|---|---|---|---|
| Valproic acid | HDAC I/IIa | ALS | Clinical trials |
| Vorinostat | HDAC | AD | Research |
| Sodium butyrate | HDAC | PD | Preclinical |
| Entinostat | HDAC | Brain tumors | Development |
Epigenetics in Neurodegenerative Diseases (2025). Subcellular Biochemistry. 2025. ↩︎
Epigenetics-Based Therapeutics for Neurodegenerative Disorders. Current Translational Geriatrics and Experimental Gerontology Reports. 2012. ↩︎
DNA Methylation in Alzheimer's Disease. Journal of Alzheimer's Disease. 2020. ↩︎
Epigenetics of Parkinson's Disease. Cellular and Molecular Life Sciences. 2018. ↩︎
5-Hydroxymethylcytosine in Brain Aging and Neurodegeneration. Nature Reviews Neuroscience. 2015. ↩︎
APP Promoter Methylation and Alzheimer's Disease. Journal of Alzheimer's Disease. 2011. ↩︎ ↩︎
SNCA Methylation and Parkinson's Disease. Neurology. 2015. ↩︎ ↩︎
C9orf72 Promoter Methylation and ALS/FTD. Neuron. 2013. ↩︎ ↩︎
HDAC2 and Memory in Alzheimer's Disease. Nature. 2012. ↩︎
TDP-43 and Epigenetic Regulation in ALS. Brain. 2019. ↩︎