|Department Affiliations||Neurology and Neuroscience|
|Rank||Professor; Co-Director, Program in NeuroRegeneration and Repair Institute for Cell Engineering|
|SOM Address||Suite 731 Miller Research Building|
Xueying Wei 1996 – 2002
Xiaojie Li 2004 – 2011
The main focus of my laboratory is to unravel the molecular basis of neurodegeneration, which parallels my clinical interest in neurodegenerative diseases. There are five broad areas of investigation including: 1) the study of the mechanisms of neuronal cell death, 2) nitric oxide (NO) signaling, 3) the study of novel cell death and cell survival pathways, 4) the study of the molecular basis of Parkinson’s disease (PD), and 5) testing innovative neuroprotective and neurorestorative strategies in PD patients. We originally identified NO as a major player in neuronal cell death and we are investigating NO-death and NO-survival signaling pathways. We showed that poly (ADP-ribose) polymerase (PARP) is a major target of NO mediated neuronal injury and showed that selective inhibitors or knockout of PARP are profoundly neuroprotective in animal models of stroke and PD. We recently identified a novel caspase-independent pathway of programmed cell death and showed that apoptosis inducing factor (AIF) is a critical cell death effector that acts downstream of NO/PARP. Current studies are focusing on the molecular mechanisms and identification of downstream targets of AIF’s actions and exploration of the role of other caspase-independent cell death effectors. We are also investigating the mechanism by which PARP activation triggers AIF release and AIF kills cells. PD is a common neurodegenerative disorder and we are studying the genetic basis of PD by investigating the mechanisms by which mutations in familial-linked genes cause PD. Mutations in a-synuclein or LRRK2 cause autosomal dominant PD and mutations in parkin, PINK1 or DJ-1 cause autosomal recessive PD. We found that parkin is an ubiquitin E3 protein ligase and that disease-causing mutations inhibit its E3 activity. We identified CDCrel-1 and synphilin-1 as parkin substrates and have shown that parkin?s E3 ligase activity may be important in the formation of Lewy bodies, the pathologic hallmark of PD. Mutations in parkin are a risk factor in sporadic PD and our discover that S-nitrosylation of parkin impairs its function links the more common sporadic form of PD with alterations in parkin function. To assess the role of parkin, PINK1 and DJ-1 in PD pathogenesis in vivo, we have knocked out DJ-1, PINK1, LRRK2 and parkin and we are identifying and characterizing protein targets of parkin and the biologic function of LRRK2, DJ-1 and PINK1.
- Chung, K.K.K, Y. Zhang, K. L. Lim, Y. Tanaka, H. Huang, J. Gao, C. A. Ross, V. L. Dawson and T. M. Dawson. “Parkin Ubiquitinates the a-Synuclein-Interacting Protein, Synphilin-1: Implications for Lewy Body Formation in Parkinson Disease.” Nature Medicine, 7:1144-1150 (2001).
- Yu, S.-W., H.-M. Wang, M.F. Poitras, C. Coombs, W.J. Bowers, H.J. Federoff, Guy G. Poirer, T.M. Dawson, V.L. Dawson ?Mediation of PARP-1 Mediated Cell Death by Apoptosis Inducing Factor.? Science, 297: 259-263 (2002).
- Dawson, T.M. and V.L. Dawson. ?Molecular Pathways of Neurodegeneration in Parkinson?s Disease? Science, 302: 819-822 (2003)
- Chung, K.K.K., B. Thomas, X. Li, O. Pletnikova, J.C. Troncoso, L. Marsh, V. L. Dawson and T.M. Dawson. ?S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin?s Protective Function.? Science, 304:1328-1331 (2004).
- Von Coelln, R., B. Thomas, J. M. Savitt, K.L. Lim, M. Sasaki, E. Hess, V.L. Dawson, T.M. Dawson. ?Loss of Locus Coeruleus Neurons and Reduced Startle in Parkin Null Mice? Proc. Natl. Acad. Sci. U.S.A., 101:10744-10749 (2004).