Loss of epigenetic adaptation to a high-fat diet in alpha-synuclein transgenic mice.

Overview

1. Department of Genetic/Epigenetics, Saarland University, Saarbrücken, Germany
2. Edwin S. H. Leong Centre for Healthy Aging, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
3. Pacific Parkinson’s Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
4. Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
5. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
6. Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital, Vancouver, BC, Canada
7. Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
8. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany

Abstract

Introduction: In humans, a high-fat diet and obesity are associated with a higher risk and accelerated progression of Parkinson’s disease (PD). Similarly, in animal models a high-fat diet exacerbates PD-related phenotypes, including dopaminergic neurodegeneration, and alpha-synuclein aggregation. We previously demonstrated that transgenic mice overexpressing human, mutated A30P alpha-synuclein failed to transcriptionally adapt to metabolic stress which could be a potential explanation for the high-fat diet-dependent aggravation of PD pathology. However, the underlying epigenetic mechanisms that might regulate this impaired response remained unknown.

Methods: Here, we profiled genome-wide DNA methylation and hydroxymethylation in brainstem and hippocampus of wild type and transgenic mice exposed to a long-term standard or high-fat diet.

Results: Wild type mice displayed pronounced diet-dependent adaptations that were largely missing in transgenic mice. In the brainstem, a high-fat diet increased the epigenetic age and induced a loss of DNA methylation of neuronal genes involved in protein degradation and mitochondrial metabolism—changes that were largely driven by DNA hydroxymethylation and absent in transgenic mice. Integration of methylation and gene expression data further revealed shared, and brain region-specific interaction networks implicated in metabolism, proteostatis, and neuronal pathways showing molecular adaptation specifically in wild type mice upon high-fat diet.

Discussion: Together, these findings point to failure of high-fat diet-induced epigenetic adaptability under alpha-synuclein overexpression, suggesting that altered DNA methylation and DNA hydroxymethylation might contribute to diet-dependent acceleration of PD pathology.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Data links

• ncbi.nlm.nih.gov/geo — NCBI; found in “Data availability statement”

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: https://www.ncbi.nlm.nih.gov/geo/, GSE313041.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 9 authors, 6 keywords, 92 references.

Cite

This paper

Hoof, V., Schaffner, S. L., Dever, K., MacIsaac, J., Rotermund, C., Kobor, M. S., Kahle, P. J., Hentrich, T., & Schulze-Hentrich, J. M. (2026). Loss of epigenetic adaptation to a high-fat diet in alpha-synuclein transgenic mice. Frontiers in cellular neuroscience, 20, 1901103. https://doi.org/10.3389/fncel.2026.1901103

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