Alpha-synuclein accumulation correlates with lipid metabolism dysregulation in mouse neurotoxicity-based models

Abstract

The accumulation and pathological aggregation of α-synuclein is a hallmark in the pathogenesis of a group of neurodegenerative disorders known as synucleinopathies, including Parkinson’s disease. Our goal was to characterize α-synuclein expression and associated metabolic changes in mouse models of neurotoxicity. To this end, we employed two neurotoxicants linked to parkinsonism: iron overload and the dithiocarbamate pesticide maneb (MB). The iron overload model was induced by repeated intraperitoneal administration of iron saccharate (333 mg/kg; 4 doses) every five days. The pesticide-induced model was established through sub-chronic exposure to MB (40 mg/kg; 12 doses), administered intraperitoneally twice a week. In both experimental models, we observed increased α-synuclein expression in mice midbrain, accompanied by a significant loss of dopaminergic neurons. This neurodegenerative process was associated with pronounced glial activation, as evidenced by elevated immunoreactivity of glial fibrillary acidic protein (GFAP) in astrocytes and ionized calcium-binding adapter molecule 1 (Iba1) in microglia. Notably, these neuropathological events were accompanied by a shift in lipid metabolism, characterized by increased levels of free cholesterol, reduced triglyceride content, and upregulation of the lipogenic transcription factors Sterol Regulatory Element Binding Protein (SREBP) 1 and 2. These lipid alterations coincided with a pronounced oxidative stress characterized by lipid peroxidation along with the activation of ferroptotic pathways, as indicated by decreased levels of glutathione peroxidase 4 (GPX4), reduced glutathione content, and downregulation of the cystine/glutamate antiporter SLC7A11. In line with these molecular changes, both the iron- and MB-treated groups exhibited significant motor deficits in rotarod and open field behavioral tests, highlighting functional impairment of the dopaminergic system in these models of neurodegeneration. Taken together, our results contribute to establish a link between lipid metabolism alterations and ferroptosis with α-synuclein accumulation in mice midbrain. These findings support the hypothesis that synucleinopathies should be considered not only as proteinopathies but also as lipidopathies