title: Autophagic activity in cortical neurons under acute oxidative stress directly contributes to cell death.
abstract: Primary neurons undergo insult-dependent programmed cell death. We examined autophagy as a process contributing to cell death in cortical neurons after treatment with either hydrogen peroxide (H(2)O(2)) or staurosporine. Although caspase-9 activation and cleavage of procaspase-3 were significant following staurosporine treatment, neither was observed following H(2)O(2) treatment, indicating a non-apoptotic death. Autophagic activity increased rapidly with H(2)O(2), but slowly with staurosporine, as quantified by processing of endogenous LC3. Autophagic induction by both stressors increased the abundance of fluorescent puncta formed by GFP-LC3, which could be blocked by 3-methyladenine. Significantly, such inhibition of autophagy blocked cell death induced by H(2)O(2) but not staurosporine. Suppression of Atg7 inhibited cell death by H(2)O(2), but not staurosporine, whereas suppression of Beclin 1 prevented cell death by both treatments, suggesting it has a complex role regulating both apoptosis and autophagy. We conclude that autophagic mechanisms are activated in an insult-dependent manner and that H(2)O(2) induces autophagic cell death.
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
authors: Gavin C
authors: GC
authors: Higgins
authors: Rodney J
authors: RJ
authors: Devenish
authors: Philip M
authors: PM
authors: Beart
authors: Phillip
authors: P
authors: Nagley
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C502661:Atg7 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008869:Microtubule-Associated Proteins; D016877:Oxidants; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D020169:Caspases; D000071193:Autophagy-Related Protein 7