α-Synuclein overexpression enhances manganese-induced neurotoxicity through the NF-κB-mediated pathway

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. alpha-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 a-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 a-synuclein expression in response to Mn exposure and to assess the role of nuclear factor-kappa B (NF-kappa B) activation as an intermediary of Mn-induced neurotoxicity. Rat mesencephalic cells (MES 23.5) overexpressing human a-synuclein show enhanced susceptibility to Mn exposure as evidenced by increased apoptosis and NF-kappa B nuclear translocation. Pretreatment with antioxidants and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 significantly diminished NF-kappa B activation, supporting a role for oxidative stress and p38 MAPK in Mn-induced NF-kappa B activation. In addition, increased nitric oxide generation was evident during NF-kappa B activation, which was blocked by NF-kappa B (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-kappa B in the mechanism of cell death. These data indicate that the transcription factor NF-kappa B, p38 MAPK, and apoptotic signaling cascades are activated by Mn in human alpha-synuclein-overexpressing cells. Thus, alpha-synuclein may facilitate Mn-induced neurotoxicity, and along with NF-kappa B, it may play a role in dopaminergic cell death.