Alpha-Synuclein attenuates Maneb neurotoxicity through the modulation of redox-sensitive transcription factors

CONDE, MELISA A.; ALZA, NATALIA P.; FUNK, MELANIA I.; MANISCALCHI, ATHINA; BENZI JUNCOS, ORIANA N.; BERGÉ, IGNACIO; URANGA, ROMINA M.; SALVADOR, GABRIELA A.

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY

LANDES BIOSCIENCE

Lugar: Austin, Texas; Año: 2023

1942-0900

The accumulation and aggregation of α-synuclein is a pathognomonic sign of Parkinson´s disease (PD). Maneb (MB) exposure has also been reported as one environmental triggering factor of this multifactorial neurodegenerative disease. In our laboratory, we have previously reported that mild overexpression of α-synuclein (200% increase with respect to endogenous neuronal levels) can confer neuroprotection against several insults. Here, we tested the hypothesis that α-synuclein can modulate the neuronal response against MB-induced neurotoxicity. When exposed to MB, cells with endogenous α-synuclein expression displayed increased reactive oxygen species (ROS) associated with diminished glutamate-cysteine ligase catalytic subunit (GCLc) and hemeoxygenase-1 (HO-1) mRNA expression and upregulation of the Nuclear Factor Erythroid 2-related Factor 2 (NRF2) repressor, BTB domain and CNC homolog 1 (BACH1). We found that α-synuclein overexpression (wt α-syn cells) attenuated MB-induced neuronal damage by reducing oxidative stress. Decreased ROS found in MB-treated wt α-syn cells were associated with unaltered GCLc and HO-1 mRNA expression and decreased BACH1 expression. In addition, the increased SOD2 expression and catalase activity were associated with Forkhead box O 3a (FOXO3a) nuclear compartmentalization. Cytoprotective effects observed in wt α-syn cells were also associated with the upregulation of silent information regulator 1 (SIRT1). In control cells, MB-treatment downregulated glutathione peroxidase 4 mRNA levels, which was coincident with increased ROS content, lipid peroxidation, and mitochondrial alterations. These deleterious effects were prevented by Ferrostatin-1 , an inhibitor of ferroptosis, under conditions of endogenous α-synuclein expression. The overexpression of α-synuclein attenuated MB-toxicity by the activation of the same mechanisms as Ferrostatin-1. Overall, our findings suggest that mild overexpression of α-synuclein attenuates MB-induced neurotoxicity through the modulation of NRF2 and FOXO3a transcription factors and prevents cell death probably by intervening in mechanisms associated with ferroptosis. Thus, we postulate that early stages of α-synuclein overexpression could be potentially neuroprotective against MB neurotoxicity.