These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: α-Synuclein overexpression enhances manganese-induced neurotoxicity through the NF-κB-mediated pathway.
    Author: Prabhakaran K, Chapman GD, Gunasekar PG.
    Journal: Toxicol Mech Methods; 2011 Jul; 21(6):435-43. PubMed ID: 21417633.
    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.
    [Abstract] [Full Text] [Related] [New Search]