Research Synopsis

My research interests are focused on neuronal cell death mechanisms in neurodegenerative diseases, such as Parkinson’s disease and Huntington’s disease. I have studied a novel neuronal injury mechanism involving nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1), and mitochondrial death protein, apoptosis-inducing factor (AIF). In response to cell death stimuli, AIF translocates to the nucleus and induces cell death in a caspase-independent manner. Excessive activation of PARP-1 is a mediator of cell death in various models of diseases, such as ischemia-reperfusion injury, glutamate excitotoxicity, diabetes, Parkinson’s disease and inflammatory processes. However, the exact mechanism by which PARP-1 induces cell death has remained elusive.

For the first time we provided the biochemical mechanism of PARP-1-initiated cell death by finding out that AIF mediates PARP-1-initiated cell death after N-methyl-D-aspartate excitotoxicity, DNA damage and oxidative stress. Moreover, poly(ADP-ribose) polymer can induce AIF release from the mitochondria and subsequent cell death in vivo and in vitro. These data provide a novel bi-directional signaling mechanism between mitochondria and nuclei for apoptosis.

Currently, I am extending my previous research into in vivo models of disease in the central nervous system, and the role of PARP-1 and AIF is being investigated in the animal and cell culture models of stroke, Parkinson’s disease and Huntington’s disease as potential therapeutic targets. Also, I am initiating a program of research aimed at understanding the mechanisms regulating the survival and death of neural stem cells. One of the main technical difficulties in stem cell therapy is poor survival of implanted stem cells. So, advances in understanding the survival and death signaling of neural stem cells may shed light on the potential application of these cells for repair of the neuronal damage. We are using adult neural stem cells derived from rat hippocampus to find the signaling mechanisms underlying neural stem cell apoptosis.

This research will lead to a better understanding of the pathogenic mechanisms of neurodegenerative diseases, and thereby provide strategies for repairing damaged human central nervous system.

Selected Publications/Abstracts since 2001

Marc F. Poitras, David W. Koh, Seong-Woon Yu, Allen S. Mandir, Guy G. Poirier, Valina L. Dawson and Ted M. Dawson. “Spatial and Functional Relationship between Poly(ADP-ribose)polymerase-1 and Poly(ADP-ribose)glycohydrogenase in the Brain.” Neuroscience 148:198-211 (2007).

Xiaoling Li, Masaaki Nemoto, Zhenfeng Xu, Seong-Woon Yu, Mika Shimoji, Shaida A. Andrabi, Jean-Francois Haince, Guy G. Poirier, Ted M. Dawson, Valina L. Dawson and Raymond C. Koehler. “Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus.” Neuroscience 144:56-65 (2007)

Seong-Woon Yu, Shaida A. Andrabi, No Soo Kim, Hongmin Wang, Guy G. Poirier, Ted M. Dawson and Valina L. Dawson. “Apoptosis Inducing Factor Mediates Poly (ADP-ribose) (PAR) Polymer Induced Cell Death”. PNAS 103:18314-18319 (2006).

Shaida A. Andrabi, No Soo Kim, Seong-Woon Yu, Hongmin Wang, David W. Koh, Masayuki Sasaki, Judith A. Klaus, Takatshi Otsuka, Zhizheng Zhang, Raymond C. Koehler, Patricia D. Hurn, Guy G. Poirier, Valina L. Dawso n, and Ted M. Dawson. “Poly (ADP-Ribose) (PAR) Polymer is a Death Signal.” PNAS 103:18308-18313 (2006).

Saskia Biskup, Darren Moore, Fulvio Celsi, Andrew West, Shaida Andrabi, Kaisa Kurkinnen, Seong-Woon Yu, Joe Savitt, Valina L. Dawson and Ted M. Dawson. “Localization of Leucine-Rich Repeat Kinase 2: Indicating a Role in Vesicular Trafficking and Membrane Recycling.” Annal Neurology 60:557-569 (2006).

Karen K. David, Masayuki Sasaki, Seong-Woon Yu, Ted M. Dawson and Valina L. Dawson. “Endonuclease G is Dispensible in Embryogenesis and Apoptosis.” Cell Death Differ. 13:1147 (2006).

Li Zhang, Mika Shimoji, Bobby Thomas, Darren J. Moore, Seong-Woon Yu, Reidun Torp, Karen M. Gujord, Ole P. Ottersen, Ted M. Dawson, and Valina L. Dawson. “Mitochondrial Localization of the Parkinson’s Disease Related Gene DJ-1: Implication for Pathogenesis.” Hum. Mol Genet. 14:2063-2073 (2005).

Xiaoling Li, Masaaki Nemoto, Seong-Woon Yu, Ted M. Dawson, Valina L. Dawson, Raymond C. Koehler. “Early Reperfusion after Focal Cerebral Ischemia Accelerates Translocation of Apoptosis-Inducing Factor to the Nucleus.” Stroke 36:510 (2005)

Seong-Woon Yu, Hongmin Wang, , Jasmine Lew, Carmen Coombs, William J. Bowers, Howard J. Federoff, Guy G. Poirier, Ted M. Dawson and Valina 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).
Seong-Woon Yu, Hongmin Wang, Ted M. Dawson and Valina L. Dawson. “Poly(ADP-ribose) Polymerase-1 and Apoptosis Inducing Factor in Neurotoxicity.” Neurobiology of Disease 14 303-317 (2003).

Hongmin Wang, Mika Shimoji, Seong-Woon Yu, Ted M. Dawson and Valina L. Dawson. “Apoptosis Inducing Factor and PARP-mediated Injury in the MPTP Mouse Model of Parkinson’s Disease.” Ann. N. Y. Acad. Sci. 991:132-139 (2003).

Sean P. Cregan, Andre Fortin, Jason G. MacLaurin, Steven M. Callaghan, Francesco Cecconi, Seong-Woon Yu, Ted M. Dawson, Valina L. Dawson, David S. Park, Guido Kroemer, and Ruth S. Slack. “Apoptosis-Inducing Factor is Involved in the Regulation of Caspase-independent Neuronal Cell Death.” J. Cell Biol. 158:507-517 (2002).