Decreased DNA methyltransferase 1 level in blood cells in Parkinson's disease

Parkinson's disease (PD) is a most common neurodegenerative disorder caused by genetic, epigenetic, and environmental factors. DNA methylation, regulated by DNA methyltransferases (DNMTs) is the key epigenetic modification playing an important role in gene expression regulation. Oligomeric alpha-synuclein - a major neurotoxic agent in PD - could sequester DNMT1 from the cell nucleus to the cytoplasm leading to global DNA hypomethylation. Here we evaluated DNMT1 expression (mRNA, protein), alpha-synuclein level, global DNA methylation in CD45+ blood cells, as well as global DNA methylation in total peripheral blood cells (TPBCs) from L-DOPA-naïve sporadic PD (sPD) patients and controls. In addition, the effect of exogenous dopamine on DNMT1 level in the nuclear (NP) and cytosolic protein (CP) fractions and DNA methylation level of SNCA intron 1 in cultured peripheral blood mononuclear cells (PBMCs) were assessed as well. We observed reduced DNMT1 protein level in CD45+ blood cells and in the CP and NP fractions of cultured PBMCs of sPD patients compared to controls. Decreased global DNA methylation in TPBCs was demonstrated in sPD compared to controls along with hypomethylation of SNCA intron 1 in cultured PBMCs of sPD patients. There was no effect of dopamine on DNMT1 level and DNA methylation level of SNCA intron 1 in cultured lymphocytes from sPD patients and controls. Alpha-synuclein level was elevated in CD45+ blood cells from sPD patients compared to controls. Our results suggested that changes in DNMT1 level in peripheral blood cells could be implicated in the PD pathogenesis.