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The Journal of Neuroscience, November 21, 2007, 27(47):12989-12999; doi:10.1523/JNEUROSCI.3400-07.2007

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Cellular/Molecular
Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal Apoptosis

Diana Steckley,^1 * Meera Karajgikar,^1 * Lianne B. Dale,¹ Ben Fuerth,¹ Patrick Swan,¹ Chris Drummond-Main,¹ Michael O. Poulter,¹ Stephen S. G. Ferguson,¹ Andreas Strasser,² and Sean P. Cregan¹

¹Robarts Research Institute and the Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 5K8, and ²The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia

Correspondence should be addressed to Dr. Sean P. Cregan, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8. Email: scregan{at}robarts.ca

Oxidative stress has been implicated as a key trigger of neuronal apoptosis in stroke and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The Bcl-2 homology 3 (BH3)-only subfamily of Bcl-2 genes consists of multiple members that can be activated in a cell-type- and stimulus-specific manner to promote cell death. In the present study, we demonstrate that, in cortical neurons, oxidative stress induces the expression of the BH3-only members Bim, Noxa, and Puma. Importantly, we have determined that Puma–/– neurons, but not Bim–/– or Noxa–/– neurons, are remarkably resistant to the induction of apoptosis by multiple oxidative stressors. Furthermore, we have determined that Bcl-2-associated X protein (Bax) is also required for oxidative stress induced cell death and that Puma plays a dominant role in regulating Bax activation. Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization. Finally, we demonstrate that whereas both Puma and Bim_EL can bind to the antiapoptotic family member Bcl-X_L, only Puma was found to associate with Bax. This suggests that in addition to neutralizing antiapoptotic members, Puma may play a dominant role by complexing with Bax and directly promoting its activation. Overall, we have identified Puma as a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis, and suggest that Puma may be an effective therapeutic target for the treatment of a number of neurodegenerative conditions.

Key words: apoptosis; Bcl-2; BH3 proteins; oxidative stress; neurodegeneration; cell death

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Received July 26, 2007; revised Sept. 20, 2007; accepted Oct. 8, 2007.

Correspondence should be addressed to Dr. Sean P. Cregan, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8. Email: scregan{at}robarts.ca

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