Dopamine controls the Sensitivity to Manganese induced Dopaminergic neurotoxicity in Caenorhabditis elegans

Manganism, a disease with characteristic degeneration of dopamine neurons, has distinct aetiology and clinical manifestations, striking similarities with Parkinsons Disease (PD). Environmental exposure to manganese (Mn) is one of the risk factors for the occurrence of PD. The definitive role of dopamine (DA) in Mn mediated neurodegeneration, and its developmental impact has not been well studied. To understand the pathways involved in Mn-induced neurotoxicity, we used C. elegans as the model system. Our results showed that adult worms treated with 50 and 100 mM MnCl2 significantly increased DA neurodegeneration. L1 larvae spared without neurodegeneration when treated with MnCl2 alone showed a significant increase in neurodegeneration (>50%) when MnCl2 exposure was given after DA pretreatment. However, both adult and larval exposure to MnCl2 demonstrated significant toxicity by reducing the survival rate. In adult worms, 100 mM MnCl2 treatment after DA pretreatment further elevated the percentage of neurodegeneration. The Mn or DA alone exposed adult worms showed recovery of neuronal dopamine function within 24 hours, although exogenous DA and Mn treated worms showed prolonged behavioural defects. Cat-2 mutants, without DA, were resistant to Mn mediated neurodegeneration. In contrast, Cat-2 overexpressing strain displayed severe neurodegeneration at lower concentrations of MnCl2 (50 mM). Our results on biochemical, behavioural and genetic assays proved endogenous/exogenous DA level controls the sensitivity to Mn induced dopaminergic neurotoxicity.