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The Journal of Neuroscience, February 14, 2007, 27(7):1519-1528; doi:10.1523/JNEUROSCI.5154-06.2007

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Neurobiology of Disease
Pancortin-2 Interacts with WAVE1 and Bcl-xL in a Mitochondria-Associated Protein Complex That Mediates Ischemic Neuronal Death

Aiwu Cheng,¹ Thiruma V. Arumugam,¹ Dong Liu,¹ Rina G. Khatri,¹ Khadija Mustafa,¹ Seung Kwak,² Huai-Ping Ling,² Cathleen Gonzales,² Ouyang Xin,¹ Dong-Gyu Jo,^1,3 Zhihong Guo,¹ Robert J. Mark,² and Mark P. Mattson^1,4

¹Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, ²Neuroscience Discovery Research, Wyeth Research, Princeton, New Jersey 08543, ³College of Pharmacy, Sungkyunkwan University, Suwon, Korea, and ⁴Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Robert J. Mark, MERCK Research Labs WP26-265, 770 Sumneytown Pike, West Point, PA 19486-0004. Email: robert_mark{at}merck.com

The actin-modulating protein Wiskott-Aldrich syndrome protein verprolin homologous-1 (WAVE1) and a novel CNS-specific protein, pancortin, are highly enriched in adult cerebral cortex, but their functions are unknown. Here we show that WAVE1 and pancortin-2 interact in a novel cell death cascade in adult, but not embryonic, cerebral cortical neurons. Focal ischemic stroke induces the formation of a protein complex that includes pancortin-2, WAVE1, and the anti-apoptotic protein Bcl-xL. The three-protein complex is associated with mitochondria resulting in increased association of Bax with mitochondria, cytochrome c release, and neuronal apoptosis. In pancortin null mice generated using a Cre-loxP system, ischemia-induced WAVE1–Bcl-xL interaction is diminished, and cortical neurons in these mice are protected against ischemic injury. Thus, pancortin-2 is a mediator of ischemia-induced apoptosis of neurons in the adult cerebral cortex and functions in a novel mitochondrial/actin-associated protein complex that sequesters Bcl-xL.

Key words: pancortin; WAVE1; cerebral ischemia; stroke; neuronal cell death; Bcl-xL

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Received Oct. 4, 2006; revised Jan. 2, 2007; accepted Jan. 2, 2007.

Correspondence should be addressed to Robert J. Mark, MERCK Research Labs WP26-265, 770 Sumneytown Pike, West Point, PA 19486-0004. Email: robert_mark{at}merck.com

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