Wassouf, Z. | bioRxiv Science

bioRxiv2021

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

BackgroundMutations and multiplications in the gene encoding for alpha-synuclein are associated with Parkinsons 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. ObjectivesTo 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. MethodsWe 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. ResultsUsing 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. ConclusionsOur 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.

genomics↗

bioRxiv2019

Enriched environmental conditions modify the gut microbiome composition and fecal markers of inflammation in Parkinson’s disease

BackgroundRecent findings suggest an implication of the gut microbiome in Parkinsons disease patients. Parkinsons disease onset and progression has also been linked with various environmental factors such as physical activity, exposure to pesticides, head injury, nicotine, and dietary factors.\n\nObjectivesIn this study, we used a transgenic mouse model overexpressing the complete human SNCA genes modeling familial and sporadic forms of Parkinsons disease to study whether environmental conditions such as standard versus enriched environment changes the gut microbiome and influences disease progression.\n\nMethodsWe performed 16S rRNA DNA sequencing on fecal samples for microbiome analysis and studied fecal inflammatory calprotectin from the colon of control and transgenic mice kept under standard environment and enriched environment conditions.\n\nResultsThe overall composition of the gut microbiota was not changed in transgenic mice compared with wild-type in enriched environment, however, individual gut bacteria at genus level such as Lactobacillus sp. were significantly changed in transgenic mice. Furthermore, enriched environment significantly reduced colon fecal inflammatory calprotectin protein in wild-type and transgenic enriched environment conditions compared to standard environment.\n\nConclusionOur data suggest that enriched social environment has a positive effect on the induction of SNCA mediated inflammation in the intestine by changing anti-inflammatory gut bacteria.

neuroscience↗