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Epigenetic Changes and Its Intervention in Age-Related Neurodegenerative Diseases

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Abstract

Epigenetic mechanisms involving the modulation of gene activity without modifying the DNA bases are reported to have lifelong effects on mature neurons in addition to their impact on synaptic plasticity and cognition. Histone methylation and acetylation are involved in synchronizing gene expression and protein function in neuronal cells. Studies have demonstrated in experimental models of neurodegenerative disorders that manipulations of these two mechanisms influence the susceptibility of neurons to degeneration and apoptosis. In Alzheimer’s disease (AD), the expression of presenilin 1 (PSEN1) is markedly increased due to decreased methylation at CpG sites, thus promoting the accumulation of toxic amyloid-β (Aβ) peptide. In Parkinson’s disease (PD), dysregulation of α-synuclein (SNCA) expression is presumed to occur via aberrant methylation at CpG sites, which controls the activation or suppression of protein expression. Mutant Huntingtin (mtHTT) alters the activity of histone acetyltransferases (HATs), causing the dysregulation of transcription observed in most Huntington’s disease (HD) cases. Folate, vitamin B6, vitamin B12, and S-adenosylmethionine (SAM) are vital cofactors involved in DNA methylation modification; 5-azacytidine (AZA) is the most widely studied DNA methyltransferase (DNMT) inhibitor, and dietary polyphenols are DNMT inhibitors in vitro. Drug intervention is believed to reverse the epigenetic mechanisms to serve as a regulator in neuronal diseases. Nevertheless, the biochemical effect of the drugs on brain function and the underlying mechanisms are not well understood. This review focuses on further discussion of therapeutic targets, emphasizing the potential role of epigenetic factors including histone and DNA modifications in the diseases.

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Abbreviations

AD:

Alzheimer’s disease

PSEN1:

Presenilin 1

PD:

Parkinson’s disease

SNCA:

α-Synuclein

mtHTT:

Mutant Huntingtin

HD:

Huntington’s disease

HDACs:

Histone deacetylases

SAM:

S-Adenosylmethionine

AZA:

5-Azacytidine

DNMT:

DNA methyltransferase

HTT:

Huntingtin

TF:

Transcription factor

CREB:

Cyclic adenosine monophosphate response element-binding protein

CBP:

CREB binding protein

HATs:

Histone acetyltransferases

FDA:

Food and Drug Administration

ASD:

Autism spectrum disorder

CGIs:

CpG islands

HHCys:

Hyperhomocysteinemia

NFTs:

Neurofibrillary tangles

PP2A:

Protein phosphatase 2A

SVs:

Synaptic vesicles

LRRK2:

Leucine-rich repeat kinase 2

CNV:

Copy number variant

ChIP-Seq:

Chromatin immunoprecipitation sequencing

HDACi:

Histone deacetylase inhibitors

BBB:

Blood–brain barrier

VA:

Valproic acid

FA:

Folic acid

AzaC:

Azacitidine

DNMTi:

DNMT inhibitors

MDS:

Myelodysplastic syndrome

NMDA:

N-Methyl-D-aspartate

T6FA:

Tacrine-6-ferulic acid

NPI:

Neuropsychiatric inventory

ADL:

Alzheimer’s Disease Cooperative Study-Activities of Daily Living

DRTs:

Dopamine replacement therapies

ICDs:

Impulse control disorders

5-aza-dC:

5-Aza-2′-deoxycytidine

RAR-β2 :

Retinoic acid receptor-β2

ATRA:

All-trans-retinoic acid

SPB:

Sodium phenylbutyrate

SAHA:

Suberoylanilide hydroxamic acid

BDNF:

Brain-derived neurotrophic factor

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Acknowledgements

This review is part of a research study financially supported by the Ministry of Higher Education Grant (FRGS/1/2019/SKK08/UKM/01/4).

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  1. Department of Biochemistry, Faculty of Medicine, Level 17 Preclinical Building, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia

    Nuraqila Mohd Murshid & Suzana Makpol

  2. Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia

    Faridah Aminullah Lubis

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  1. Nuraqila Mohd Murshid
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Mohd Murshid, N., Aminullah Lubis, F. & Makpol, S. Epigenetic Changes and Its Intervention in Age-Related Neurodegenerative Diseases. Cell Mol Neurobiol 42, 577–595 (2022). https://doi.org/10.1007/s10571-020-00979-z

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