This presentation briefly describes the involvement of epigenetic mechanisms in Parkinson's disease and their potential role in regulating disease progression

1. EPIGENETIC MECHANISMS IN
PARKINSONS DISEASE
PRESENTED BY :
Uppala Sai Nikhil
RT/2021/614
MS pharm 1st yr.
Regulatory Toxicology
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UNDER GUIDANCE OF
Dr. Dharmendra khatri

2. EPIGENETICS
 Epigenetics is defined as study of potentially stable, ideally heritable change in gene expression or cellular phenotype
that occurs without any changes in DNA base pairs.
Mechanisms of epigenetic
modifications
DNA methylation Histone modification
Inhibition of
gene expression
Gene expressed
Decondensed
–active
chromatin
Condensed
– inactive
chromatin
2
Evangalia et al,Front. Genet., 18 September

3. Factors inducing epigenetic modifications
Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. Front Cell Dev Biol. 2014 Sep 9;2:49.
doi: 10.3389/fcell.2014.00049.
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4. 4
EPIGENETIC MODIFICATIONS IN PD GENES
Aayana singh et al,Neurochem Res.
 Parkinson's is a neurodegenerative disease characterized by motor symptoms such as tremors, rigidity and
bradykinesia and non motor symptoms like issues in GIT and mental health.

5. 5
Chiara et alInt. J. Mol. Sci. 2013, 14(9), 17643-17663 Zhu X, Chen et al,Signal Transduct Target Ther. 2021 Jun
DNA methylation in PD pathology

6. DNA methylation in PD
• DNA methylation involves addition of methyl groups at cpg dinucleotides that are majorly present at the
promoter region.
• Many genes involved in PD undergo methylation and demethylation at specific sites which are major causes for
sporadic form of Parkinsons disease.
5- cytosine
S-adenosyl methionine(SAM)
DNA methyl transferase(DNMT)
SAH
5-methyl cytosine
Hyper methylation- PGC-1𝛼
TRIM10
GFPT2
TMEM9
MAPT
Hypo methylation – Cyp2E1
TNF- 𝛼
SNCA
PARK-2
Hemant et al, Genes 2019, 10(2), 172
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7. SNCA gene
hypomethylated in SNPC
Upregulation of gene by
transcription factors
Increased alpha-synuclein
production
Sequesters DNMT in
cytoplasm and prevents
gene methylation
Alpha synuclein aggregation
and mitochondrial dysfunction
Dopaminergic neuronal cell
death
DNA samples from substantia
nigra and cortex from 6PD
patients and 6 neurologically
active individuals
Bisulfite sequencing of
SNCA introns
Results revealed only 1-2 %
of CpG dinucleotides are
methylated
↓DNMT levels in nucleus
Epigenetic modifications on SNCA gene
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Ganguly et al,. Drug Design, Development and Therapy. 2017.

8. • Decreased expression of DNMT1 levels in PD is evidenced by ELISA assays.
• The mis localization of DNMT is limited to neuronal cells which is evidenced using neuronal (NeuN) marker.
Paula et al, JBC Papers in Press, February 4, 2011
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9. TeT2
overexpression
Activation of Cdkn2A
pathway
Activation of
transcripts(P14,P16)
Dopaminergic
neuronal injury
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Fig showing accumulation of TET2 in nucleus and increased TET2 upon MPTP treatment
Human Molecular Genetics, Volume 29, Issue 8, 15 April 2020,

10. In PD condition
PGC-1alpha
Hypermethylation
Mt transcription factors cannot
access the DNA
Decreased Mitochondrial biogenesis
Mitochondrial dysfunction
Compromised antioxidant defence
Dysregulation of ER stress
and inflammatory signalling
Neuro inflammation
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Qi, Zhengtang & Ding, Shuzhe et al,.PPAR research. 2012. 348245. 10.1155/2012.

11. • Genomic DNA isolated upon bisulfite sequencing showed that PGC-1α hypermethylation in substantia nigra of PD
patients when compared with controls.
• Unlike the most methylations ,Cpg dinucleotides are unaffected rather they were non canonical methylated residues
and results showed an increase in methylation by 1.6 times.
• PGC-1 alpha expression was also found to decrease by 53% in PD when compared with controls due to hyper
methylation.
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Su, Xiaomin & Chu et al,journal pLoS ONE. Aug 2015

12. • Studies made in adult mice where a knockdown of DNMT3A showed reduced levels of CpH methylation
but not CpG methylation.
• Another hypothesis is that increased free fatty acids concentration also increases hypermethylation of
PGC-1 alpha.
Palmitate added to neuronal cultures in 0.1
and 0.5mM concentrations
DNA isolation and bisulfite
sequencing performed
0.5mM concn palmitate showed significant
methylation in promotor region of PGC1 alpha
Methylation at promotor increased by 180.2%
compared to control with 0.5mM conc
PGC-1alpha gene expression was decreased by
89.1% when compared to PBS control
Ratio of Mt DNA to nuclear DNA decreased by
49.7% compared to control
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Su, Xiaomin & Chu et al,journal pLoS ONE. Aug 2015

13. CYP2E1 hypomethylation in PD
Cyp2E1
hypomethylation
Expression increased in
basal ganglia
Produces toxic metabolites and
produces free radical
metabolism
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Oliver et al,Life 2022, 12(4), 502
Shah et al, Curr Drug Metab. 2021
Fig showing CYP2E1 expression
Fig showing ↓ 𝛼synuclein levels in K.O mice

14. • MAPT gene is majorly associated with idiopathic PD where its over expression causes tau protein deposition.
• In studies performed by Coupland they focused on aberrant methylation of MAPT gene where it showed diplotype
specific, gender specific patterns of methylation.
• Sex specific MAPT methylation is an independent predictor of disease onset but higher methylation in women
compared to men explains the reason for more susceptibility of men to PD.
• H1/H1 diplotype is more methylated than H2/H2 diplotype which explains the diplotype specific pattern of
methylation which could be due to presence of more CpG dinucleotides in the former region.
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15.  PARK16 locus has 5 genes of which 3(RAB29,SLC41A1,NUCKS1) are differentially methylated involved in PD
pathogenesis.
 RAB29 methylation causes over recruitment of LRRK2 and increased lysosomal autophagy. However SLC41A1 which is
involved in mg homeostasis if downregulated leads to neurodegeneration.
 In contrast, NUCKS1 overexpression leads to increased activation of inflammatory immune response pathways.
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16. Reversing
epigenetic
modification
5-azatidine
zebularine
MG98
RG108
Protein methyl
transferase inhibitors
BIX-01294
UNC0646
UNCO638
Diet rich in folates
and methionine
HDAC inhibitors
Ex-short chain FA
Hydroximic acids
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Hegarty et al,Neural Regen Res. 2016
Nov;11

17. LEVODOPA ↑Methylation in SNCA gene
SIRTUIN
SIRT 1
Regulate Mt activation
Inhibit oxidative stress
PGC-alpha
activation
SIRT2
Inhibits alpha
synuclein toxicity
Epigallocatechin
DNMT and HAT inhibitor
Inhibits TNFalpha,IL-𝛽
IL-6.
Activates astrocytes
caffeine
↑Dopamine content
↓Proinflammatory cells
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Liu Y et al, Front Aging Neurosci. 2020 Jan10.

18. • On a final note, epigenetics is more of an experience related heritable changes that alter gene expression,
many other biological factors and enzymes also influence epigenetic mechanisms which one way or the
other involve in disease progression.
• Moreover, many of the gene modifications were found to be age related, gender specific and also based on
the dietary factors.
• Many studies were done which provide a base evidence for epigenetic mechanisms in disease related genes
which help unveil the targets for therapy.
• In contrast natural agents such as phytochemicals, vitamins are found to much helpful for reducing the
disease progression. maintaining a balanced and healthy lifestyle can probably protect from many epigenetic
diseases.
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19. 1. Paula Desplats, Brian Spencer, Elizabeth Coffee, Pruthul Patel, Sarah Michael, Christina Patrick, Anthony Adame, Edward Rockenstein,
Eliezer Masliah,α-Synuclein Sequesters Dnmt1 from the Nucleus: A NOVEL MECHANISM FOR EPIGENETIC ALTERATIONS IN LEWY BODY
DISEASES*,Journal of Biological Chemistry,https://doi.org/10.1074/jbc.C110.212589.
2. Heerboth S, Lapinska K, Snyder N, Leary M, Rollinson S, Sarkar S. Use of epigenetic drugs in disease: an overview. Genet Epigenet.
2014;6:9-19. Published 2014 May 27. doi:10.4137/GEG.S12270
3. Wu TT, Liu T, Li X, Chen YJ, Chen TJ, Zhu XY, Chen JL, Li Q, Liu Y, Feng Y, Wu YC. TET2-mediated Cdkn2A DNA hydroxymethylation in mid
brain dopaminergic neuron injury of Parkinson's disease. Hum Mol Genet. 2020 May 28;29(8):1239-1252. doi: 10.1 093/hmg/dda a02
2.Erratum in: Hum Mol Genet. 2021 Jun 9;30(12):1172-1173. PMID: 32037456.
4. Su X, Chu Y, Kordower JH, Li B, Cao H, Huang L, Nishida M, Song L, Wang D, Federoff HJ. PGC-1α Promoter Methylation in Parkinson's
Disease. PLoS One. 2015 Aug 28;10(8):e0134087. doi: 10.1371/journal.pone.0134087. PMID: 26317511; PMCID: PMC4552803.
5. Kaut, Oliver and Schmitt, Ina and Stahl, Fabian and Fröhlich, Holger and Hoffmann, Per and Gonzalez, Frank J. and Wüllner,
Ullrich,Epigenome-Wide Analysis of DNA Methylation in Parkinson DiseaseCortex,Life,12,2022,4.
6. Pieper HC, Evert BO, Kaut O, Riederer PF, Waha A, Wüllner U. Different methylation of the TNF-alpha promoter in cortex
and substantia nigra: Implications for selective neuronal vulnerability. Neurobiol Dis. 2008 Dec;32(3):521-7. doi:
10.1016/j.nbd.2008.09.010. Epub 2008 Sep 30. PMID: 18930140.
7. Coupland, K. G., Mellick, G. D., Silburn, P. A., Mather, K., Armstrong, N. J., Sachdev, P. S., Brodaty, H., Huang, Y., Halliday, G. M., Hallupp,
M., Kim, W. S., Dobson-Stone, C., & Kwok, J. B. (2014). DNA methylation of the MAPT gene in Parkinson's disease cohorts and
modulation by vitamin E in vitro. Movement disorders : official journal of the Movement Disorder Society, 29(13), 1606–1614.
https://doi.org/10.1002/mds.25784
8. Goldstein O, Gana-Weisz M, Casey F, Meltzer-Fridrich H, Yaacov O, Waldman YY, Lin D, Mordechai Y, Zhu J, Cullen PF,
Omer N, Shiner T, Thaler A, Bar-Shira A, Mirelman A, John S, Giladi N, Orr-Urtreger A. PARK16 locus: Differential effects
of the non-coding rs823114 on Parkinson's disease risk, RNA expression, and DNA methylation. J Genet Genomics. 2021
Apr 20;48(4):341-345. doi: 10.1016/j.jgg.2020.10.010. Epub 2021 Jan 29. PMID: 33736926.
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