PMID- 37113744 OWN - NLM STAT- MEDLINE DCOM- 20230501 LR - 20230501 IS - 1942-0994 (Electronic) IS - 1942-0900 (Print) IS - 1942-0994 (Linking) VI - 2023 DP - 2023 TI - alpha-Synuclein Attenuates Maneb Neurotoxicity through the Modulation of Redox-Sensitive Transcription Factors. PG - 5803323 LID - 10.1155/2023/5803323 [doi] LID - 5803323 AB - The accumulation and aggregation of alpha-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 alpha-synuclein (200% increase with respect to endogenous neuronal levels) can confer neuroprotection against several insults. Here, we tested the hypothesis that alpha-synuclein can modulate the neuronal response against MB-induced neurotoxicity. When exposed to MB, cells with endogenous alpha-synuclein expression displayed increased reactive oxygen species (ROS) associated with diminished glutamate-cysteine ligase catalytic subunit (GCLc) and hemeoxygenase-1 (HO-1) mRNA expressions and upregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) repressor, BTB domain and CNC homolog 1 (BACH1). We found that alpha-synuclein overexpression (wt alpha-syn cells) attenuated MB-induced neuronal damage by reducing oxidative stress. Decreased ROS found in MB-treated wt alpha-syn cells was associated with unaltered GCLc and HO-1 mRNA expressions 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 alpha-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 alpha-synuclein expression. The overexpression of alpha-synuclein attenuated MB toxicity by the activation of the same mechanisms as ferrostatin-1. Overall, our findings suggest that mild overexpression of alpha-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 alpha-synuclein overexpression could be potentially neuroprotective against MB neurotoxicity. CI - Copyright (c) 2023 M. A. Conde et al. FAU - Conde, M A AU - Conde MA AUID- ORCID: 0000-0001-7766-687X AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. AD - Universidad Nacional del Sur (UNS), Departamento de Biologia, Bioquimica y Farmacia, Bahia Blanca, Argentina. FAU - Alza, N P AU - Alza NP AUID- ORCID: 0000-0002-2705-8777 AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. AD - UNS, Departamento de Quimica, Bahia Blanca, Argentina. FAU - Funk, M I AU - Funk MI AUID- ORCID: 0000-0002-3127-7892 AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. AD - Universidad Nacional del Sur (UNS), Departamento de Biologia, Bioquimica y Farmacia, Bahia Blanca, Argentina. FAU - Maniscalchi, A AU - Maniscalchi A AUID- ORCID: 0000-0002-1921-0337 AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. FAU - Benzi Juncos, O N AU - Benzi Juncos ON AUID- ORCID: 0000-0002-7698-5075 AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. AD - Universidad Nacional del Sur (UNS), Departamento de Biologia, Bioquimica y Farmacia, Bahia Blanca, Argentina. FAU - Berge, I AU - Berge I AUID- ORCID: 0000-0002-0234-9930 AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. AD - Universidad Nacional del Sur (UNS), Departamento de Biologia, Bioquimica y Farmacia, Bahia Blanca, Argentina. FAU - Uranga, R M AU - Uranga RM AUID- ORCID: 0000-0002-8113-4646 AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. AD - Universidad Nacional del Sur (UNS), Departamento de Biologia, Bioquimica y Farmacia, Bahia Blanca, Argentina. FAU - Salvador, G A AU - Salvador GA AUID- ORCID: 0000-0002-5475-4655 AD - National Scientific and Technical Research Council-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina. AD - Universidad Nacional del Sur (UNS), Departamento de Biologia, Bioquimica y Farmacia, Bahia Blanca, Argentina. LA - eng PT - Journal Article DEP - 20230418 PL - United States TA - Oxid Med Cell Longev JT - Oxidative medicine and cellular longevity JID - 101479826 RN - 0 (alpha-Synuclein) RN - 0 (ferrostatin-1) RN - 0 (Reactive Oxygen Species) RN - 12427-38-2 (Maneb) RN - 0 (NF-E2-Related Factor 2) SB - IM MH - Humans MH - alpha-Synuclein/metabolism MH - Reactive Oxygen Species/metabolism MH - *Maneb MH - *Neurodegenerative Diseases MH - NF-E2-Related Factor 2/genetics/metabolism MH - Oxidation-Reduction MH - *Neurotoxicity Syndromes PMC - PMC10129426 COIS- The authors declare that they have no conflict of interest. EDAT- 2023/04/28 06:41 MHDA- 2023/05/01 06:42 PMCR- 2023/04/18 CRDT- 2023/04/28 02:34 PHST- 2022/06/24 00:00 [received] PHST- 2023/02/02 00:00 [revised] PHST- 2023/02/06 00:00 [accepted] PHST- 2023/05/01 06:42 [medline] PHST- 2023/04/28 06:41 [pubmed] PHST- 2023/04/28 02:34 [entrez] PHST- 2023/04/18 00:00 [pmc-release] AID - 10.1155/2023/5803323 [doi] PST - epublish SO - Oxid Med Cell Longev. 2023 Apr 18;2023:5803323. doi: 10.1155/2023/5803323. eCollection 2023.