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.

Bcl2L12 with a BH3-like domain in regulating apoptosis and TMZ-induced autophagy: A prospective combination of ABT-737 and TMZ for treating glioma

“…However, it may inhibit the phosphorylation on Bcl2 family members to affect the level of these proteins. Moreover, STS induce more abundantly caspase-dependent apoptotic events in the primary cortical neurons (42). This can be part of the reason why the effect attributed to protein-protein interaction of Bcl2 family proteins is lacking.…”

Rapamycin and Interleukin-1β Impair Brain-derived Neurotrophic Factor-dependent Neuron Survival by Modulating Autophagy

“…The major form of autophagy, macroautophagy, is a constitutive form of self-digestion that is activated by nutrient starvation, accumulation of misfolded proteins, or mTOR inhibition. Autophagy is an essential component of the stress response of cells (19,20); however, excessive autophagy can lead to cell death (21)(22)(23)(24). There is evidence that autophagy is impaired in Alzheimer disease (25), and inhibitors of mTOR such as rapamycin are reported to induce autophagic clearance of pathogenic proteins in neurodegenerative diseases (26,27).…”

Oxidative stress impairs autophagic flux in prion protein-deficient hippocampal cells

“…It was recently reported that H 2 O 2 induces autophagic cell death with elevated autophagic activity in primary cortical neurons. 57 However, it is reasonable to propose that enhanced autophagy could eliminate oxidized or damaged intracellular components as a cellular defense mechanism against oxidative stress.…”