Oxidative Stress Induces Neuronal Death by Recruiting a Protease and Phosphatase-gated Mechanism

Reactive oxygen species (ROS) cause death of cerebellar granule neurons. Here, a 15-min pulse of H2O2 (100 μm) induced an active process of neuronal death distinct from apoptosis. Oxidative stress activated a caspase-independent but calpain-dependent decline of calcium/calmodulin-dependent protein k...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-09, Vol.276 (37), p.35049-35059
Main Authors: Sée, Violaine, Loeffler, Jean-Philippe
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Calcineurin - physiology
Calcium-Calmodulin-Dependent Protein Kinases - analysis
Calpain - physiology
Caspases - physiology
Cyclic AMP Response Element-Binding Protein - analysis
Cyclic AMP Response Element-Binding Protein - metabolism
Hydrogen Peroxide - toxicity
Life Sciences
Mice
Necrosis
Neurons - pathology
Oxidative Stress
Phosphoprotein Phosphatases - physiology
Phosphorylation
Protein Biosynthesis
Serine - metabolism
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Summary:Reactive oxygen species (ROS) cause death of cerebellar granule neurons. Here, a 15-min pulse of H2O2 (100 μm) induced an active process of neuronal death distinct from apoptosis. Oxidative stress activated a caspase-independent but calpain-dependent decline of calcium/calmodulin-dependent protein kinase IV and cAMP- responsive element-binding protein (CREB). Calpain inhibitors restored calcium/calmodulin-dependent protein kinase IV and CREB but did not influence phosphorylated CREB levels or survival, indicating recruitment of an additional dephosphorylation process. Co-treatment with calpain and serine/threonine phosphatase inhibitors restored pCREB levels and rescued neurons. This phosphatase-activated signaling pathway was shown to be dependent on de novo protein synthesis. Further, gene transfer studies revealed that CREB is a common final effector of both apoptosis and ROS-induced death. Our data indicate that dephosphorylation and proteolytic signaling mechanisms underlie ROS-induced programmed cell death.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M104988200