Epigenetic Mechanisms in Neurodegenerative Diseases

Epigenetic regulation comprises reversible chemical modifications to DNA and histone proteins that influence gene activity without altering the underlying sequence. In neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and related tauopathies, aberrant DNA methylation patterns and dysregulated histone modifications contribute to neuronal dysfunction, synaptic loss and cognitive decline. Age-related shifts in chromatin state can accelerate pathological processes by altering enhancer activity, disrupting transcriptional networks and promoting neuroinflammation. Recent work has revealed that loss of specific histone marks at genes implicated in protein homeostasis and neuronal survival, combined with region- and cell type–specific methylation changes at risk loci, underlies disease susceptibility and progression. The dynamic interplay between epigenetic drift in ageing brains and genetic risk variants shapes the landscape of gene expression in affected regions, offering both mechanistic insight and novel targets for biomarker development and therapeutic intervention.

Research from Nature Portfolio

A study in a mouse model of tauopathy demonstrated that the histone methyltransferase Smyd3 is upregulated in prefrontal cortex and drives excessive H3K4 trimethylation at synaptic genes. Pharmacological inhibition of Smyd3 restored NMDAR function, rescued cognitive deficits and normalised expression of the E3 ubiquitin ligase target Fbxo2, unveiling an integrated mechanism that links epigenetic enzymes to proteostatic control in Alzheimer-like pathology. Complementing this, fine-mapping of enhancer methylation in human prefrontal cortex neurons revealed widespread loss of non-CpG methylation at enhancers in Alzheimer’s disease, notably within a cluster of regulatory elements in the DSCAML1 locus that increases BACE1 transcription, amyloid burden and cognitive impairment. Foundational work comparing normal ageing and Alzheimer’s disease brains has established that age-associated enrichment of histone H4 lysine 16 acetylation is reversed in disease, with locus-specific losses correlating with genetic risk variants and expression quantitative trait loci at key neurodegeneration genes.

Epigenetic Mechanisms in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in epigenetic mechanisms in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

DNA methylation: Addition of methyl groups to cytosine bases, commonly at CpG sites, that modulates gene expression by altering chromatin accessibility.

Histone modification: Covalent changes (e.g. acetylation, methylation) to histone tails that influence nucleosome structure and transcriptional activity.

Enhancer: A DNA regulatory element that enhances transcription of a distal gene by recruiting transcription factors and co-activators.

Chromatin accessibility: The openness of chromatin, dictating the ease with which transcriptional machinery and regulatory proteins can bind DNA.

CpG site: A dinucleotide sequence where cytosine is followed by guanine, frequently subject to methylation and key to epigenetic regulation.

References

1. Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease. Molecular Neurodegeneration (2024).
2. Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model. Nature Communications (2023).
3. Role of primary aging hallmarks in Alzheimer´s disease. Theranostics (2023).
4. Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nature Neuroscience (2018).
5. DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex. Epigenetics & Chromatin (2018).
6. Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms. Nature Communications (2019).