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

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.