Abstract
Parkinson’s disease (PD) and dementia with Lewy body (DLB) are the most common synucleinopathies. SNCA gene is a major genetic risk factor for these diseases group, and dysregulation of its expression has been implicated in the genetic etiologies of several synucleinopathies. DNA methylation at CpG island (CGI) within SNCA intron 1 has been suggested as a regulatory mechanism of SNCA expression, and changes in methylation levels at this region were associated with PD and DLB. However, the role of DNA methylation in the regulation of SNCA expression in a cell-type specific manner and its contribution to the pathogenesis of PD and DLB remain poorly understood, and the data are conflicting. Here, we employed a bisulfite pyrosequencing technique to profile the DNA methylation across SNCA intron 1 CGI in PD and DLB compared to age- and sex-matched normal control subjects. We analyzed homogenates of bulk post-mortem frozen frontal cortex samples and a subset of neuronal and glia nuclei sorted by the fluorescence-activated nuclei sorting (FANS) method. Bulk brain tissues showed no significant difference in the overall DNA methylation across SNCA intron 1 CGI region between the neuropathological groups. Sorted neuronal nuclei from PD frontal cortex showed significant lower levels of DNA methylation at this region compared to normal controls, but no differences between DLB and control, while sorted glia nuclei exhibited trends of decreased overall DNA methylation in DLB only. In conclusion, our data suggested disease-dependent cell-type specific differential DNA methylation within SNCA intron 1 CGI. These changes may affect SNCA dysregulation that presumably mediates disease-specific risk. Our results can be translated into the development of the SNCA intron 1 CGI region as an attractive therapeutics target for gene therapy in patients who suffer from synucleinopathies due to SNCA dysregulation.
Highlights
Synucleinopathies are a group of neurodegenerative disorders that share a pathological hallmark of intracellular inclusions, composed largely of the α-synuclein protein (SNCA), known as Lewy bodies (LBs) and Lewy-related neurites (Spillantini et al, 1997; Spillantini, 1999; Galvin et al, 2001; Jellinger, 2003; Marti et al, 2003)
DNA Methylation Levels at the SNCA Intron 1 CpG island (CGI) in Bulk Brain Tissue Homogenates From Parkinson’s disease (PD) and dementia with Lewy body (DLB) Compared to Control
We found for the first-time disease-dependent cell type-specific differential DNA methylation profiles in the CGI located in SNCA intron 1
Summary
Synucleinopathies are a group of neurodegenerative disorders that share a pathological hallmark of intracellular inclusions, composed largely of the α-synuclein protein (SNCA), known as Lewy bodies (LBs) and Lewy-related neurites (Spillantini et al, 1997; Spillantini, 1999; Galvin et al, 2001; Jellinger, 2003; Marti et al, 2003). DNA methylation is an epigenetic mechanism of gene regulation, and several groups have studied the DNA methylation profiles of SNCA intron 1 region in relation to SNCA expression in the context of PD and DLB. Other reported no significant differences in the DNA methylation levels within SNCA intron 1 in postmortem brain tissues from PD vs controls (Guhathakurta et al, 2017). These conflicting results may stem from several reasons such as sample size, the analyzed tissue type and/or brain structure, and the sensitivity and accuracy of the method used for profiling the DNA methylation. The variability in the proportion of the different cell types is even more pronounced in samples from brains affected by neurodegeneration
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