Autophagic activity in cortical neurons under acute oxidative stress directly contributes to cell death |
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Authors: | Gavin?C?Higgins Rodney?J?Devenish Philip?M?Beart Email author" target="_blank">Phillip?NagleyEmail author |
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Institution: | (1) Department of Biochemistry and Molecular Biology, Monash University, Building 13D, Clayton Campus, Clayton, VIC, 3800, Australia;(2) Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia;(3) Florey Neuroscience Institutes, University of Melbourne, Parkville, VIC, 3010, Australia;(4) Department of Pharmacology, University of Melbourne, Parkville, VIC, 3010, Australia; |
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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 (H2O2) or staurosporine. Although caspase-9 activation and cleavage of procaspase-3 were significant following staurosporine treatment,
neither was observed following H2O2 treatment, indicating a non-apoptotic death. Autophagic activity increased rapidly with H2O2, 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 H2O2 but not staurosporine. Suppression of Atg7 inhibited cell death by H2O2, 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 H2O2 induces autophagic cell death. |
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