Objective: This study aimed to compare the DNA methylome of Lewy body dementia (LBD) patients and healthy controls.

Background: LBD is the second most common neurodegenerative dementia following Alzheimer’s disease. LBD patients present with heterogeneous clinical features, including cognitive, neuropsychiatric, motor, and autonomic symptoms. Genetic risk factors have recently been implicated in the etiology of LBD, but the role of epigenetic mechanisms is still unknown.
DNA methylation is an epigenetic mechanism able to modulate gene expression. Specifically, methylation at a gene promoter is usually associated with gene silencing, while gene body methylation typically increases gene expression.

Method: We compared 101 pathologically confirmed LBD patients and 91 neurologically healthy controls. The mean age of death was 80 years for each group. Males and females were equally distributed in our study cohort. We hybridized 450 ng of bisulfite-converted DNA, extracted from cerebellar cortex, to Infinium MethylationEPIC Beadchips (Illumina). The raw data were preprocessed in Genome Studio (Illumina) and exported to the R package ‘minfi’ for further analysis. We excluded low-quality samples (p-value > 0.05), probes located on X-Y chromosomes, and probes that failed in at least one individual.

Results: A total of 816,126 probes were available for the analysis. We detected 5,328 differentially methylated probes (p-value < 9×10-8) in 3,941 genes: 4,903 (92%) were hypermethylated and 425 (8%) were hypomethylated in LBD patients. Differential DNA methylations mainly affected biological processes implicated in cell projection morphogenesis and neuron projection development (adj. p-value < 10-6), and cellular components such as cell junctions and synapses (adj. p-value < 10-5). Notably, the gene PTPRN2 showed 17 gene body modulated probes, of which 15 were hypermethylated.
We next examined 94 genes associated with neurodegenerative disorders. We found that 48 probes showed differential methylation, of which 45 were hypermethylated. These signals mainly involved the genes PARK2, WWOX, FYN and MED12L.

Conclusion: Preliminary results from our study show a clear cerebellar DNA hypermethylation signature in LBD patients compared to controls, suggesting that epigenetic regulation plays an important role in LBD pathogenesis. These insights may pave the way for the identification of new molecular pathways that could be targeted for the development of novel therapeutics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/differential-methylation-signatures-in-lewy-body-dementia/