Skip Navigation


ToxSci Advance Access originally published online on May 4, 2007
Toxicological Sciences 2007 98(2):495-509; doi:10.1093/toxsci/kfm099
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
98/2/495    most recent
kfm099v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Choi, C. J.
Right arrow Articles by Kanthasamy, A. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Choi, C. J.
Right arrow Articles by Kanthasamy, A. G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Normal Cellular Prion Protein Protects against Manganese-Induced Oxidative Stress and Apoptotic Cell Death

Christopher J. Choi*, Vellareddy Anantharam*, Nathan J. Saetveit{dagger}, Robert S. Houk{dagger}, Arthi Kanthasamy* and Anumantha G. Kanthasamy*,1

* Neuroscience and Toxicology Graduate Programs, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, College of Veterinary Medicine {dagger} Ames Laboratory, U.S. Department of Energy, Department of Chemistry, Iowa State University, Ames, Iowa 50011

1 To whom correspondence should be addressed at Neuroscience and Toxicology Graduate Programs, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, 2062 Veterinary Medicine Bldg., Iowa State University, Ames, IA 50011. Fax: (515) 294-2315. E-mail: akanthas{at}iastate.edu.

Received February 22, 2007; accepted April 19, 2007


  Abstract

The normal prion protein is abundantly expressed in the central nervous system, but its biological function remains unclear. The prion protein has octapeptide repeat regions that bind to several divalent metals, suggesting that the prion proteins may alter the toxic effect of environmental neurotoxic metals. In the present study, we systematically examined whether prion protein modifies the neurotoxicity of manganese (Mn) by comparing the effect of Mn on mouse neural cells expressing prion protein (PrPC-cells) and prion-knockout (PrPKO-cells). Exposure to Mn (10µM–10mM) for 24 h produced a dose-dependent cytotoxic response in both PrPC-cells and PrPKO-cells. Interestingly, PrPC-cells (EC50 117.6µM) were more resistant to Mn-induced cytotoxicity, as compared to PrPKO-cells (EC50 59.9µM), suggesting a protective role for PrPC against Mn neurotoxicity. Analysis of intracellular Mn levels showed less Mn accumulation in PrPC-cells as compared to PrPKO-cells, but no significant changes in the expression of the metal transporter proteins transferrin and DMT-1. Furthermore, Mn-induced mitochondrial depolarization and reactive oxygen species (ROS) generation were significantly attenuated in PrPC-cells as compared to PrPKO-cells. Measurement of antioxidant status revealed similar basal levels of glutathione (GSH) in PrPC-cells and PrPKO-cells; however, Mn treatment caused greater depletion of GSH in PrPKO-cells. Mn-induced mitochondrial depolarization and ROS production were followed by time- and dose-dependent activation of the apoptotic cell death cascade involving caspase-9 and -3. Notably, DNA fragmentation induced by both Mn treatment and the oxidative stress inducer hydrogen peroxide (100µM) was significantly suppressed in PrPC-cells as compared to PrPKO-cells. Together, these results demonstrate that prion protein interferes with divalent metal Mn uptake and protects against Mn-induced oxidative stress and apoptotic cell death.

Key Words: manganese; neurotoxicity; prion disease; metals; ROS; caspases.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.