Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway.

Authors: Chen, L  Liu, L  Yin, J  Luo, Y  Huang, S 
Citation: Chen L, etal., Int J Biochem Cell Biol. 2009 Jun;41(6):1284-95. doi: 10.1016/j.biocel.2008.10.029. Epub 2008 Nov 6.
Pubmed: (View Article at PubMed) PMID:19038359
DOI: Full-text: DOI:10.1016/j.biocel.2008.10.029

Oxidative stress-induced neuronal apoptosis is a prominent feature found in neurodegenerative disorders. However, how oxidative stress induces neuronal apoptosis is not well understood. To address this question, undifferentiated and differentiated neuronal cell lines (PC12 and SH-SY5Y) were exposed to hydrogen peroxide (H(2)O(2)), a major oxidant generated when oxidative stress occurs. We observed that H(2)O(2) induced generation of reactive oxygen species (ROS), leading to apoptosis of the cells in a concentration- and time-dependent manner. H(2)O(2) rapidly activated the mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38. Inhibition of Erk1/2, JNK or p38 with kinase inhibitors (U0126, SP600125 or PD169316, respectively), downregulation of Erk1/2 or p38 using RNA interference, or expression of dominant negative c-Jun partially prevented H(2)O(2)-induced apoptosis. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged H(2)O(2)-induced ROS, blocking activation of MAPKs and cell death. Furthermore, we found that H(2)O(2)-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented H(2)O(2)-activation of Erk/12, JNK and p38, as well as cell death. Similar results were observed in primary murine neurons as well. The results suggest that H(2)O(2)-induction of ROS inhibit PP2A and PP5, leading to activation of Erk1/2, JNK and p38 pathways thereby resulting in neuronal apoptosis. Our findings suggest that inhibitors of MAPKs (JNK, Erk1/2 and p38), activators of phosphatases (PP2A and PP5) or antioxidants may have potentials to prevent and treat oxidative stress-induced neurodegenerative diseases.


Gene Ontology Annotations
Objects Annotated

Additional Information

CRRD Object Information
CRRD ID: 8694078
Created: 2014-07-23
Species: All species
Last Modified: 2014-07-23
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.