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

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

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY

LANDES BIOSCIENCE

Año: 2023

1942-0900

The accumulation and aggregation of α-synuclein is a pathognomonic sign of Parkinson´sdisease (PD). Maneb (MB) exposure has also been reported as one environmental triggeringfactor of this multifactorial neurodegenerative disease. In our laboratory, we have previouslyreported that mild overexpression of α-synuclein (200% increase with respect to endogenousneuronal levels) can confer neuroprotection against several insults. Here, we tested thehypothesis that α-synuclein can modulate the neuronal response against MB-inducedneurotoxicity. When exposed to MB, cells with endogenous α-synuclein expression displayedincreased reactive oxygen species (ROS) associated with diminished glutamate-cysteine ligasecatalytic subunit (GCLc) and hemeoxygenase-1 (HO-1) mRNA expression and upregulation ofthe Nuclear Factor Erythroid 2-related Factor 2 (NRF2) repressor, BTB domain and CNChomolog 1 (BACH1). We found that α-synuclein overexpression (wt α-syn cells) attenuatedMB-induced neuronal damage by reducing oxidative stress. Decreased ROS found in MBtreated wt α-syn cells were associated with unaltered GCLc and HO-1 mRNA expression anddecreased BACH1 expression. In addition, the increased SOD2 expression and catalase activitywere associated with Forkhead box O 3a (FOXO3a) nuclear compartmentalization.Cytoprotective effects observed in wt α-syn cells were also associated with the upregulation ofsilent information regulator 1 (SIRT1). In control cells, MB-treatment downregulatedglutathione peroxidase 4 mRNA levels, which was coincident with increased ROS content, lipidperoxidation, and mitochondrial alterations. These deleterious effects were prevented byFerrostatin-1 , an inhibitor of ferroptosis, under conditions of endogenous α-synucleinexpression. The overexpression of α-synuclein attenuated MB-toxicity by the activation of thesame mechanisms as Ferrostatin-1. Overall, our findings suggest that mild overexpression of αsynuclein attenuates MB-induced neurotoxicity through the modulation of NRF2 and FOXO3atranscription factors and prevents cell death probably by intervening in mechanismsassociated with ferroptosis. Thus, we postulate that early stages of α-synuclein overexpressioncould be potentially neuroprotective against MB neurotoxicity.