Methylmercury (MeHg) is a well-known neurotoxicant but the diverse mechanistic events associated with MeHg neurotoxicity have yet been fully elucidated. In this study, we explored the mechanisms of MeHg neurotoxicity particularly its possible roles in neurodegenerative diseases like Parkinson’s disease (PD) using dopaminergic neuronal cells and a non-human primate model. In the cell culture model, we compared effects of MeHg to those induced by 1-methyl-4-phenylpyridinium (MPP⁺), a well-established drug that can induce Parkinsonism-like symptoms. A proteomic approach was used to identify and analyze MeHg affected proteins and their biological functions and associated pathways in both the cellular and marmoset models. Our results showed that MeHg induced changes of gene/protein profiles are similar to the effects as MPP⁺. Evidence from proteomic results suggested MeHg caused neurodegenerative effects not only associated with PD but also other neurodegenerative disorders such as Huntington’s disease (HD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). We also found brain regional specific response to MeHg stimuli, based on the protein profiles affected in the following order: cerebellum > occipital lobe (OL) > frontal lobe (FL) of the cerebrum. In the cerebellum, carbohydrate derivative metabolic process, synaptic transmission, cell development and calcium signalling are dominant functions and pathways contributing to the motor deficit in MeHg-treated marmoset. MeHg was found to selectively target membrane proteins in the cerebellum particularly in synaptic membranes. MeHg affected proteins involved in energy metabolism in both OL and FL of the cerebrum through different proteins and biochemical pathways. In the OL, proteins were enriched in functions of carbohydrate metabolic process, lipid metabolic process, cellular amino acid metabolic process, homeostatic process, transportation, and regulation of body fluid level. In the FL, differentially expressed proteins were mainly involved in the cell cycle and cell division, glycerolipid metabolic process, sulfur compound metabolic process, cellular amino acid metabolic process, microtubule-based process, and proteolysis. The dyshomeostasis of water transport and associated pathways observed in OL and FL was found to be the underlying mechanism for brain edema observed in the MeHg exposed marmoset. Novel proteins such as DLG4 (PSP95) in the cerebellum and APOE in OL were exhibited to be core proteins in linking multifunction targeted by MeHg. This study provides a new perspective upon understanding mechanisms behind MeHg mediated neurotoxic deficits, and suggests potential links between MeHg exposure and neurodegenerative disorders in humans.
