Methylation of MAPT Gene in Neurodegenerative Synucleinopathies

Synucleinopathies are neurodegenerative disorders characterized by the accumulation of pathological aggregates of alpha-synuclein protein in central nervous system cells. Parkinson’s disease (PD) and multiple system atrophy (MSA) are the most common variants of synucleinopathies. The exact causes of these disorders are still unknown, but it is well established that both genetic and environmental factors are involved. Both polymorphisms in the MAPT gene and dysregulation of epigenetic mechanisms, particularly, methylation of transcription regulation regions of the genes, are risk factors of synucleinopathy development. We examined the influence of methylation level of the MAPT gene on the development of PD and MSA and performed a clinical and epigenetic comparison. We identified hypermethylation of three CpG sites in the promotor region of the MAPT gene in the group of MSA patients in comparison with controls. We also identified significant differences in methylation level of four CpG sites in the promotor region between MAPT haplotypes in the MSA group, and the protective H2 haplotype was hypomethylated. The modifying role of age and antiparkinsonian therapy with dopamine receptor agonists on the methylation level of the MAPT gene was established. The data obtained in comparative analysis of the methylation level in the group of synucleinopathies indicate the potential protective role of MAPT hypomethylation, as we found predominantly hypomethylated status of CpG sites in the control group, hypomethylation of protective H2 allele of the MAPT gene, and age-dependent increase in hypermethylation.