Figure 3: Schematic shows the potential role of epigenetic mechanism that may be involved in manganese induced chronic neurotoxic effects and in pathology of Parkinson’s disease. The steady state level of Mn transporter (DMT1) is maintained by PARK2/parkin ubiquitin E3-ligase. miR-34b/c regulates the expression of PARK2. Loss of its expression can make the cells susceptible to elevated uptake of Mn. DJ1 works as an oxidative stress sensor which is again regulated by miR-34b/c; hence deregulation in miR-34b/c expression can make the cell vulnerable to oxidative stress. Mn induced oxidative stress causes the overexpression of α-synuclein via ERK/MAPK pathway or through epigenetic alteration in miR-7/miR-153 expression which regulates α-syn gene. Oxidative stress may also cause the hypomethylation of CpG islands at intron 1 of SNCA gene resulting in α-synuclein overexpression. Expression of α-synuclein is regulated by fibroblast growth factor 20 (FGF20) which is in turn regulated by miR-433. The single nucleotide polymorphism (SNP) at binding site of miR-433 disturbs epigenetic regulation of FGF20 causing α-synuclein overexpression. α-Synuclein under the influence of oxidative stress can form α-syn oligomers which leads to Golgi complex fragmentation and subsequent impairment in dopamine transporter biosynthesis and trafficking. α-Synuclein at cytoplasm binds to antiapoptotic 14-3-3, making proapoptotic BAD cause mitochondrial impairment. α-Synuclein is reported to sequester DNMT1 in cytoplasm which results in global hypomethylation of genes including those associated with Parkinson’s disease (SNCA, PARK2, etc.). α-Synuclein expressed at physiological level is supposed to participate in cell survival via regulating proapoptotic PKCδ expression through epigenetic mechanism. α-Synuclein at nucleus binds to histone proteins and inhibits activity of histone acetyltransferase, causing deregulation of PKCδ expression. The inhibition of PKCδ expression resulted in DNA fragmentation followed by apoptotic cell death.