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Alpha-synuclein overexpression is associated with epigenomic dysregulation of glutamate signaling and locomotor pathways

ABSTRACT: Although Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders, interindividual differences in PD etiology related to genetics are not fully understood. Here, we demonstrate genome-wide DNA methylation and hydroxymethylation alterations associated with overexpression of two PD-linked alpha-synuclein variants (wild type and A30P) in LUHMES cells differentiated to dopaminergic neurons. Alpha-synuclein altered DNA methylation at thousands of CpGs and DNA hydroxymethylation at hundreds of CpGs in both genotypes, and primarily at locomotor and glutamate signaling pathway genes. In some cases, epigenetic changes were associated with transcription. SMITE network analysis incorporating H3K4me1 ChIP-seq to score DNA methylation and hydroxymethylation changes across promoters, enhancers, and gene bodies confirmed epigenetic and transcriptional deregulation of glutamate signaling modules in both genotypes. Our results identify distinct and shared impacts of alpha-synuclein variants on the epigenome, and associate alpha-synuclein in the epigenetic etiology of PD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181126 | GEO | 2021/08/02

REPOSITORIES: GEO

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