Hypomethylation of intron1 of α-synuclein gene does not correlate with Parkinson’s disease

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Abstract

Deregulation of α-synuclein encoding gene ( SNCA) is one of the important facets of Parkinson’s disease (PD) research. DNA methylation status of SNCA-intron1 has been shown to regulate the α-synuclein expression. The present study is aimed at investigating whether methylation of SNCA-intron1 is associated with higher expression of α-synuclein in PD. We have investigated the intron1 methylation status from 16 post-mortem brain samples comprised of 8 PD and 8 control subjects using bisulfite sequencing. We further correlated this methylation status with α-synuclein protein levels in substantia nigra of that individual using western blot analysis. We did not observe any significant difference in methylation of SNCA-intron1 region between PD and control samples. Moreover, no correlation was observed between methylation of SNCA-intron1 with α-synuclein level. Methylation of SNCA-intron1 region does not correlate with α-synuclein expression in PD samples.

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Methylation regulates alpha-synuclein expression and is decreased in Parkinson's disease patients' brains.

Ahmad Jowaed, Ina Schmitt, Oliver Kaut … (2010)

Alpha-synuclein (SNCA) is a major risk gene for Parkinson's disease (PD), and increased SNCA gene dosage results in a parkinsonian syndrome in affected families. We found that methylation of human SNCA intron 1 decreased gene expression, while inhibition of DNA methylation activated SNCA expression. Methylation of SNCA intron 1 was reduced in DNA from sporadic PD patients' substantia nigra, putamen, and cortex, pointing toward a yet unappreciated epigenetic regulation of SNCA expression in PD.

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Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases.

Sarah Michael, Brian Spencer, Eliezer Masliah … (2011)

DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of α-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of α-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and α-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in α-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB.

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CpG Demethylation Enhances Alpha-Synuclein Expression and Affects the Pathogenesis of Parkinson's Disease

Lumine Matsumoto, Hiroshi Takuma, Akira Tamaoka … (2010)

Background Alpha-synuclein (SNCA) gene expression is an important factor in the pathogenesis of Parkinson's disease (PD). Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD. CpG methylation in the promoter region may also influence SNCA expression. Methodology/Principal Findings By using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression. Postmortem brain analysis revealed regional non-specific methylation differences in this CpG region in the anterior cingulate and putamen among controls and PD; however, in the substantia nigra of PD, methylation was significantly decreased. Conclusions/Significance This CpG region may function as an intronic regulatory element for SNCA gene. Our findings suggest that a novel epigenetic regulatory mechanism controlling SNCA expression influences PD pathogenesis.

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Contributors

Subhrangshu Guhathakurta: subhrangshu.guhathakurta@ucf.edu

Baggio A. Evangelista: bevangelista@knights.ucf.edu

Susmita Ghosh: susmita_ghosh@knights.ucf.edu

Sambuddha Basu: sambuddha.basu@knights.ucf.edu

Yoon-Seong Kim: 407-266-7070 , Yoon-Seong.kim@ucf.edu

Journal

Journal ID (nlm-ta): Mol Brain

Journal ID (iso-abbrev): Mol Brain

Title: Molecular Brain

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-6606

Publication date (Electronic): 7 February 2017

Publication date PMC-release: 7 February 2017

Publication date Collection: 2017

Volume: 10

Electronic Location Identifier: 6

Affiliations

[1 ]ISNI 0000 0001 2159 2859, GRID grid.170430.1, Division of Neurosciences, Burnett School of Biomedical Sciences, , University of Central Florida College of Medicine, ; 6900 Lake Nona Blvd, Orlando, FL 32827 USA

[2 ]ISNI 0000 0001 2171 7818, GRID grid.289247.2, , Kyunghee University Medical College, ; Seoul, Korea

Article

Publisher ID: 285

DOI: 10.1186/s13041-017-0285-z

PMC ID: 5297217

PubMed ID: 28173842

SO-VID: 87562c00-b17e-4888-8fb3-7898410246f2

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 8 December 2016

Date accepted : 14 January 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: 5R21NS088923-02

Award Recipient : Yoon-Seong Kim

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ScienceOpen disciplines: Neurosciences

Keywords: epigenetic regulation,dna methylation,parkinson’s disease,α-synuclein

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ScienceOpen disciplines: Neurosciences

Keywords: epigenetic regulation, dna methylation, parkinson’s disease, α-synuclein

Hypomethylation of intron1 of α-synuclein gene does not correlate with Parkinson’s disease

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Alternative approaches to Alzheimer's Disease

Most cited references 12

Methylation regulates alpha-synuclein expression and is decreased in Parkinson's disease patients' brains.

Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases.

CpG Demethylation Enhances Alpha-Synuclein Expression and Affects the Pathogenesis of Parkinson's Disease

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