title: Role of autophagy in arsenite-induced neurotoxicity: the involvement of α-synuclein.
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 (MMA(III)), and dimethyl arsenate (DMA(V)) were compared as follows: MMA(III)>arsenite»arsenate and DMA(V). 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.
authors: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors: Yu-Chun
authors: YC
authors: Teng
authors: Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan.
authors: Chung Jiuan
authors: CJ
authors: Jeng
authors: Department of Medical Research, Taipei-Veterans General Hospital, Taipei, Taiwan.
authors: Hui-Ju
authors: HJ
authors: Huang
authors: Department of Medical Research, Taipei-Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Electronic address: myalin@vghtpe.gov.tw.
authors: Anya Maan-Yuh
authors: AM
authors: Lin
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D000071193:Autophagy-Related Protein 7; D005260:Female; D008869:Microtubule-Associated Proteins / Q000032:analysis; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044764:Ubiquitin-Activating Enzymes / Q000502:physiology; D051844:alpha-Synuclein / Q000032:analysis / Q000502:physiology*
chemical_list: D018053:Arsenites; D000071193:Autophagy-Related Protein 7; D008869:Microtubule-Associated Proteins; D044764:Ubiquitin-Activating Enzymes; D051844:alpha-Synuclein; C561242:Atg7 protein, rat; C526109:Anxa3 protein, rat; C015001:arsenite
keywords: Arsenite; Atg7siRNA transfection; Autolysosome; Autophagy; Neurotoxicity; α-Synuclein