Maneb-induced neurotoxicity involves dopaminergic cell loss and impaired lipid metabolism

In vivo pesticide toxicity is considered a suitable experimental paradigm for studying Parkinson's disease-related disorders. Maneb (MB), a dithiocarbamate pesticide, has been associated with Parkinsonism in rural populations environmentally exposed to this fungicide. We have previously reported MB-evoked ferroptosis in neurons. In this study, we show that MB-exposed mice exhibited impaired locomotor activity and motor coordination. Consistent with these findings, the midbrain of mice sub-chronically exposed to MB displayed markers of oxidative stress, molecular components of ferroptosis, neuroinflammation, and impaired lipid metabolism. The loss of dopaminergic neurons in the midbrain was accompanied by increased cholesterol levels and decreased triacylglycerol content. Alongside these lipid alterations, we also observed astrogliosis and elevated α-synuclein expression and phosphorylation. Overall, our results indicate that lipid disturbances occur in MB-treated mice because of increased oxidative stress. These findings suggest that impaired lipid metabolism is a biomarker of neurodegeneration associated with pesticide exposure and movement disorders. Our results align with emerging evidence that lipidopathies are important contributors to neurodegeneration in Parkinson's disease-related disorders. The in vivo model characterized in this study provides a valuable tool for exploring novel therapeutic strategies aimed at preventing neurodegeneration driven by oxidative stress and associated with lipid metabolism rewiring.