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The Journal of Neuroscience, September 28, 2005, 25(39):8954-8966; doi:10.1523/JNEUROSCI.2899-05.2005

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Neurobiology of Disease
Differential Roles of Nuclear and Cytoplasmic Cyclin-Dependent Kinase 5 in Apoptotic and Excitotoxic Neuronal Death

Michael J. O'Hare,¹ Neena Kushwaha,¹ Yi Zhang,¹ Hossein Aleyasin,¹ Steven M. Callaghan,¹ Ruth S. Slack,¹ Paul R. Albert,¹ Inez Vincent,² and David S. Park¹

¹Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa Health Research Institute, Neuroscience Group, Ottawa, Ontario, Canada K1H 8M5, and ²The Nathan Shock Center of Excellence in the Basic Biology of Aging and Department of Pathology, University of Washington, Seattle, Washington 98195

Cyclin-dependent kinase 5 (cdk5) is a member of the cyclin-dependent kinase family whose activity is localized mainly to postmitotic neurons attributable to the selective expression of its activating partners p35 and p39. Deregulation of cdk5, as a result of calpain cleavage of p35 to a smaller p25 form, has been suggested to be a central component of neuronal death underlying numerous neurodegenerative diseases. However, the relevance of cdk5 in apoptotic death that relies on the mitochondrial pathway is unknown. Furthermore, evidence that cdk5 can also promote neuronal survival has necessitated a more complex understanding of cdk5 in the control of neuronal fate. Here we explore each of these issues using apoptotic and excitotoxic death models. We find that apoptotic death induced by the DNA-damaging agent camptothecin is associated with early transcription-mediated loss of p35 and with late production of p25 that is dependent on Bax, Apaf1, and caspases. In contrast, during excitotoxic death induced by glutamate, neurons rapidly produce p25 independent of the mitochondrial pathway. Analysis of the localization of p35 and p25 revealed that p35 is mainly cytoplasmic, whereas p25 accumulates selectively in the nucleus. By targeting a dominant-negative cdk5 to either the cytoplasm or nucleus, we show that cdk5 has a death-promoting activity within the nucleus and that this activity is required in excitotoxic death but not apoptotic death. Moreover, we also find that cdk5 contributes to pro-survival signaling selectively within the cytoplasm, and manipulation of this signal can modify death induced by both excitotoxicity and DNA damage.

Key words: apoptosis; cell cycle; p35; cdk5; excitotoxicity; DNA damage

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Received Feb 23, 2005; revised August 16, 2005; accepted August 17, 2005.

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