Epigenetic Changes and Its Intervention in Age-Related Neurodegenerative Diseases
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REVIEW PAPER
Epigenetic Changes and Its Intervention in Age‑Related Neurodegenerative Diseases Nuraqila Mohd Murshid1 · Faridah Aminullah Lubis2 · Suzana Makpol1 Received: 18 July 2020 / Accepted: 6 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Epigenetics · Alzheimer’s disease · Parkinson’s disease · Huntington’s disease · DNA methylation · Histone deacetylase 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
* Suzana Makpol [email protected] 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
Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia
2
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
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