Journal Article

DZNE-2026-00905

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of epigenetic adaptation to a high-fat diet in alpha-synuclein transgenic mice.

Hoof, V. ; Schaffner, S. L. ; Dever, K. ; MacIsaac, J. ; Rotermund, C.DZNE* ; Kobor, M. S. ; Kahle, P.Extern* ; Hentrich, T. ; Schulze-Hentrich, J. M.

2026
Frontiers Research Foundation Lausanne

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Please use a persistent id in citations: doi:10.3389/fncel.2026.1901103

Abstract: 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.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.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.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.

Keyword(s): DNA hydroxymethylation ; DNA methylation ; Parkinson’s disease ; alpha-synuclein ; epigenetics ; high-fat diet

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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