Role of autophagy in arsenite-induced neurotoxicity: The involvement of α-synuclein

Yu Chun Teng, Chung Jiuan Jeng, Hui Ju Huang, Anya Maan Yuh Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

In the present study, the role of autophagy in sodium arsenite (arsenite)-induced neurotoxicity was investigated in rat primary cultured cortical neurons. Incubation with arsenite concentration-dependently increased LC3-II levels (a biomarker of autophagy), indicating that arsenite is capable of inducing autophagy. Co-localization of fluorescent puncta of monodansylcadaverine (a fluorescent dye of autophagic vacuoles) and LysoTracker Red (a fluorescent dye of lysosomes) as well as chloroquine-induced enhancement of arsenite-elevated LC3-II levels suggest that arsenite induced autolysosome formation in primary cultured cortical neurons. Incubation of 3-methyladenine (an autophagy inhibitor) prevented arsenite-induced LC3-II elevation, autolysosome formation, reduction in GAP 43 (a biomarker of neurite outgrowth), caspase 3 activation and neuronal cell loss. Furthermore, Atg7 siRNA transfection attenuated arsenite-induced autophagy and neurotoxicity. At the same time, Atg7siRNA transfection ameliorated arsenite-induced reduction in α-synuclein levels (a synaptic protein essential for neuroplasticity), suggesting that arsenite via autophagy may engulf α-synuclein. Cytotoxic activities as well as potencies in elevating LC3-II and reducing α-synuclein levels by arsenite, arsenate, monomethyl arsenite (MMAIII), and dimethyl arsenate (DMAV) were compared as follows: MMAIIIarsenite»arsenate and DMAV. Taken together, autophagy appears to play a pro-death role in arsenics-induced neurotoxicity. Moreover, autophagy and subsequent reduction in α-synuclein levels may be a vicious cycle in arsenics-induced neurotoxicity.

Original languageEnglish
Pages (from-to)239-245
Number of pages7
JournalToxicology Letters
Volume233
Issue number3
DOIs
StatePublished - 8 Mar 2015

Keywords

  • Arsenite
  • Atg7siRNA transfection
  • Autolysosome
  • Autophagy
  • Neurotoxicity
  • α-Synuclein

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