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Alpha-synuclein induces epigenomic dysregulation of glutamate signaling and locomotor pathways

View ORCID ProfileSamantha L. Schaffner, Zinah Wassouf, Diana F. Lazaro, Mary Xylaki, Nicole Gladish, David T. S. Lin, Julia MacIsaac, Katia Ramadori, Julia M. Schulze-Hentrich, Tiago F. Outeiro, Michael S. Kobor
doi: https://doi.org/10.1101/2021.06.12.448150
Samantha L. Schaffner
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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  • ORCID record for Samantha L. Schaffner
Zinah Wassouf
2Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany
3German Centre for Neurodegenerative Diseases (DZNE), Göttingen, Germany
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Diana F. Lazaro
2Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany
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Mary Xylaki
2Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany
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Nicole Gladish
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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David T. S. Lin
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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Julia MacIsaac
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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Katia Ramadori
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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Julia M. Schulze-Hentrich
4Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
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Tiago F. Outeiro
2Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany
3German Centre for Neurodegenerative Diseases (DZNE), Göttingen, Germany
5Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany
6Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK
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  • For correspondence: msk@bcchr.ca touteir@gwdg.de
Michael S. Kobor
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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  • For correspondence: msk@bcchr.ca touteir@gwdg.de
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Abstract

Background Mutations and multiplications in the gene encoding for alpha-synuclein are associated with Parkinson’s disease (PD). However, not all individuals with alpha-synuclein variants develop PD, suggesting that additional factors are involved. We hypothesized that increased alpha-synuclein might alter epigenetic regulation of PD pathways.

Objectives To identify genome-wide DNA methylation and hydroxymethylation changes induced by overexpression of two alpha-synuclein variants in human dopaminergic neurons, and to relate these to the corresponding transcriptome.

Methods We assessed DNA methylation and hydroxymethylation at >850,000 CpGs using the EPIC BeadChip in LUHMES cells differentiated to dopaminergic neurons. Control LUHMES neurons, LUHMES neurons overexpressing wild type alpha-synuclein, and LUHMES neurons overexpressing A30P alpha-synuclein were compared. We used SMITE network analysis to identify functionally related genes with altered DNA methylation, DNA hydroxymethylation, and/or gene expression, incorporating LUHMES H3K4me1 ChIP-seq to delineate enhancers in addition to the default promoter and gene body regions.

Results Using stringent statistical thresholds, we found that increased expression of wild type or A30P mutant alpha-synuclein induced DNA methylation changes at thousands of CpGs and DNA hydroxymethylation changes at hundreds of CpGs. Differentially methylated sites in both genotypes were enriched for several processes including movement-associated pathways and glutamate signaling. For glutamate and other signaling pathways (i.e. PDGF, insulin), this differential DNA methylation was also associated with transcriptional changes.

Conclusions Our results indicated that alpha-synuclein altered the DNA methylome of dopaminergic neurons, influencing regulation of pathways involved in development, signaling, and metabolism. This supports a role for alpha-synuclein in the epigenetic etiology of PD.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Financial Disclosure/Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  • Funding: This research was conducted under a Transnational “Epigenomics of Complex Diseases” grant (CIHR EGM-141897, ANR-15-EPIG-0001, BMBF 01KU1503A). TFO is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2067/1- 390729940, and SFB1286 (Project B6).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Alpha-synuclein induces epigenomic dysregulation of glutamate signaling and locomotor pathways
Samantha L. Schaffner, Zinah Wassouf, Diana F. Lazaro, Mary Xylaki, Nicole Gladish, David T. S. Lin, Julia MacIsaac, Katia Ramadori, Julia M. Schulze-Hentrich, Tiago F. Outeiro, Michael S. Kobor
bioRxiv 2021.06.12.448150; doi: https://doi.org/10.1101/2021.06.12.448150
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Alpha-synuclein induces epigenomic dysregulation of glutamate signaling and locomotor pathways
Samantha L. Schaffner, Zinah Wassouf, Diana F. Lazaro, Mary Xylaki, Nicole Gladish, David T. S. Lin, Julia MacIsaac, Katia Ramadori, Julia M. Schulze-Hentrich, Tiago F. Outeiro, Michael S. Kobor
bioRxiv 2021.06.12.448150; doi: https://doi.org/10.1101/2021.06.12.448150

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