Downregulation of redox-sensitive transcription factors and neuronal ferroptosis as underlying mechanisms of maneb-induced toxicity

CONDE, M.; BENZI JUNCOS, O.N.; MANISCALCHI, A.; FUNK, M.I.; ALZA, N.P.; SALVADOR, G.

San Luis

Congreso; XXXVIII SAN 2023 Meeting; 2023

Epidemiological studies provide evidence of a strong association between the use of dithiocarbamate pesticides, such as Maneb (MB), and the risk of Parkinson’s disease. Here, we tested the hypothesis that MB increases α-synuclein expression and downregulates several redox-sensitive transcription factors, thus promoting neuronal death. For this purpose, we challenged neuronal and primary glial cultures, and mice with MB. When exposed to MB, neurons showed α-synuclein upregulation accompanied by markers of oxidative stress. This was associated with diminished glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 mRNA expression and upregulation of the NRF2 repressor, BACH1. MB treatment also downregulated glutathione peroxidase 4 mRNA levels in neurons, which was coincident with increased content of reactive oxygen species, lipid peroxidation, and mitochondrial alterations. These deleterious effects were prevented by treating MB-exposed neurons with ferrostatin-1, an inhibitor of ferroptosis. In glial cell cultures, MB triggered microglial and astrocyte activation. In mice, MB-induced neurodegeneration provoked motor impairment associated with enhanced α-synuclein expression in midbrain. Our results show that MB-induced neurotoxicity downregulates NRF2 pathway and elicits neuronal death probably triggering mechanisms associated with ferroptosis.