Valina Dawson, Ph.D. Professor Department of Neurology Department of Neuroscience Department of Physiology Institute For Cell Engineering 733 North Broadway, Suite 711 Baltimore, MD 21205 Phone: (410) 614-3361 (office) Fax: (410) 614-9568 Email: vdawson@jhmi.edu Neuroscience web page CMM web page

Research Summary

Molecular Mechanisms of Neuronal Death and Survival

Neurons that are Preconditioned are Remarkably Resistant to Neurotoxicity and AIF does not Translocate to the Nucleus. These preconditioned cultures were exposed to neurotoxic concentrations of NMDA yet they are alive and AIF is retained in the mitochondria. New gene products regulate this profound neuronal survival.

The brain is the most complex organ in the body and allows us to interact with the world around us. Unlike many other tissues, neurons are not routinely or easily replaced. When neurons are lost due to trauma or disease there is a significant loss of function. In order to treat patients suffering neurologic dysfunction it will be necessary to accomplish several integrated goals including: (1) understanding the cellular death signaling pathways to reveal potential drugable targets for pharmaceutical intervention, (2) understanding endogenous survival pathways to learn how to induce these pathways to provide complimentary or alternative therapeutic targets, (3) to learn how nerves regenerate and find their appropriate targets, (4) to restore full function it may be necessary to replace the neurons that have been lost.

The research projects in my laboratory focus on these targets towards discovering new treatment strategies for neurologic injury. Our neurotoxicity model focuses on ischemic (loss of glucose and oxygen) and excitotoxic injury. We have identified a highly choreographed signal cascade triggered by glutamate acting at the NMDA receptor, stimulating neuronal nitric oxide synthase that triggers lethal peroxynitrite generation and poly(ADP-ribose) polymerase activation. We have recently described a new interaction between nuclear activation of poly(ADP-ribose) polymerase and mitochondrial release of apoptosis inducing factor, in the integration of the death signal. Our models of Parkinson’s disease focus on understanding how mutations in particular genes result in Parkinson’s disease through the generation of genetically engineered mice and biochemical and cell biology approaches.

To understand survival signaling in the brain, we have undertaken gene discovery projects utilizing methods developed in the laboratory to understand the genes and proteins that are responsible for mediating the profound protection afforded to the brain by the phenomena of preconditioning. These screens have yielded a cornucopia of new survival proteins that have not previously been realized to participate in brain survival. We are currently characterizing these genes and proteins to better understand their biology as well as identify potential targets to develop new therapeutics to protect the brain.

Neural precursor or stem cells provide promise and hope that lost neurons can be replaced. However, many of these cells die before they integrate into the host. We have conducted a genetic screen using an siRNA library and have uncovered a collection of new cell death molecules. We are beginning to investigate these new death proteins in order to understand cell death programs in neural precursor, stem cells as well as the brain. These studies are integrated with ongoing investigations into neuronal death and survival pathways.

Selected Recent Publications

• Wang, H., S.W. Yu, D.W. Koh, J. Lew, C. Coombs, W. Bowers, H.J. Federoff, G.G. Poirier, T.M. Dawson, and V.L. Dawson. “Apoptosis Inducing Factor (AIF) Substitutes for Caspase Executioners in N- methyl- D- aspartate Triggered Excitotoxic Neuronal Death.” J. Neurosci. 24: 10963- 10973 (2004).

• 2. Koh, D.W., A.M. Lawler, M.F. Poitras, M. Sasaki, S. Wattler, M.C. Nehls, T. Stöger, G.G. Poirier, T.M. Dawson and V.L. Dawson. "Failure to Degrade Poly(ADP- ribose) Causes Increased Sensitivity to Cytotoxicity and Early Embryonic Lethality.” Proc. Natl. Acad. Sci. U.S.A. 101(51): 17699- 17704 (2004).

• 3. Biskup, S, D.J. Moore, F. Celsi, S. Higashi, A.B. West, S.A. Andrabi, K. Kurkinen, S.- W. Yu, J.M. Savitt, H.J. Waldvogel, R.L.M. Faull, P.C. Emson, R. Torp, O.P. Ottersen, T.M. Dawson, and V.L. Dawson. “Localization of LRRK2 Indicates a Role in Vesicular Trafficking and Membrane Recycling.” Ann. Neurol., 60(5):557- 569 (2006).

• 4. Yu, S.W., S.A. Andrabi, H. Wang, N.S. Kim, G.G. Poirier, V.L. Dawson and T.M. Dawson. “Apoptosis Inducing Factor (AIF) Mediates Poly (ADP- ribose) (PAR) Polymer Induced Cell Death” Proc. Natl. Acad. Sci. U.S.A. 103: 18314–18319 (2006).

• 5. Anrabi, S., N.S. Kim, S.W. Yu, N.S. Kim, H. Wang, D. Koh, M. Sasaki, J.A. Klaus, T. Otsuka, Z. Zhang, R.C. Koehler, P. Hurn, G.G. Poirier, V.L. Dawson and T.M. Dawson. “Poly (ADP- ribose) (PAR) Polymer is a Novel Death Signal.” Proc. Natl. Acad. Sci. U.S.A. 103:18308–18313 (2006).

• 6. West, A.B., D.J. Moore, C. Choi, S.A. Andrabi, X. Li, D. Dikeman, S. Biskup, Z. Zhang, K- L. Lim, V.L. Dawson, T.M. Dawson. “Parkinson's disease- associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.” Hum. Mol. Genet.