Failure of diet-induced transcriptional adaptations in A30P alpha-synuclein transgenic mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA810724 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18150900.fastq.gz | Fastqsanger.gz | |||
| SRR18150901.fastq.gz | Fastqsanger.gz | |||
| SRR18150902.fastq.gz | Fastqsanger.gz | |||
| SRR18150903.fastq.gz | Fastqsanger.gz | |||
| SRR18150904.fastq.gz | Fastqsanger.gz |
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Project description: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 adaptions 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 adaption 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.
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Project description:Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected. Factorial design comparing SNCA knock-out mice with wild type littermates in two different tissues (striatum, cerebellum) at two different timepoints (6 and 21 month)
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