title: α-Synuclein overexpression enhances manganese-induced neurotoxicity through the NF-κB-mediated pathway.
abstract: Exposure to manganese (Mn) occurs in both civilian and military operations. Mn exposure results in a movement disorder termed manganism, which resembles Parkinson's disease (PD). However, the pathogenic mechanisms underlying this disorder are not fully understood. α-Synuclein, a presynaptic protein is implicated in some neurodegenerative disorders, including PD and Mn-induced apoptosis, and its overexpression contributes to the loss of dopaminergic neurons. Although the role of α-synuclein in this process is widely documented, its exact function is not clear. The objective of this study was to evaluate the mechanism(s) of dopaminergic degeneration associated with α-synuclein expression in response to Mn exposure and to assess the role of nuclear factor-κB (NF-κB) activation as an intermediary of Mn-induced neurotoxicity. Rat mesencephalic cells (MES 23.5) overexpressing human α-synuclein show enhanced susceptibility to Mn exposure as evidenced by increased apoptosis and NF-κB nuclear translocation. Pretreatment with antioxidants and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 significantly diminished NF-κB activation, supporting a role for oxidative stress and p38 MAPK in Mn-induced NF-κB activation. In addition, increased nitric oxide generation was evident during NF-κB activation, which was blocked by NF-κB (SN50) and MAPK inhibitors. Mn-induced cell death was attenuated by SN-50 and specific nitric oxide synthase (NOS) inhibitor (1400W); corroborating NOS activation is mediated through NF-κB in the mechanism of cell death. These data indicate that the transcription factor NF-κB, p38 MAPK, and apoptotic signaling cascades are activated by Mn in human α-synuclein-overexpressing cells. Thus, α-synuclein may facilitate Mn-induced neurotoxicity, and along with NF-κB, it may play a role in dopaminergic cell death.
authors.affiliation: Naval Medical Research Unit Dayton (NAMRU-D), Wright-Patterson Air Force Base, Dayton, OH 45433, USA.
authors.forename: Krishnan
authors.initials: K
authors.lastname: Prabhakaran
authors.forename: Gail D
authors.initials: GD
authors.lastname: Chapman
authors.forename: Palur G
authors.initials: PG
authors.lastname: Gunasekar
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity; D020260:Heavy Metal Poisoning, Nervous System / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D006822:Hybrid Cells; D008345:Manganese / Q000633:toxicity*; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000975:Antioxidants; D004785:Environmental Pollutants; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; C497604:SNCA protein, human; D051844:alpha-Synuclein; D009569:Nitric Oxide; D008345:Manganese; D048051:p38 Mitogen-Activated Protein Kinases