Center for Global Health Faculty
Ted Dawson
Director of the Program in Neuroregeneration and Repair
Academic Degrees
Departmental Address
733 N Broadway #731
Baltimore, MD 21205
Research and Professional Experience
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. We are identifying and characterizing protein targets of parkin and the biologic function of LRRK2, DJ-1 and PINK1.
Keywords
Nitric Oxide, Poly (ADP-ribose) polymerase, AIF, Parkinson's Disease, Stroke, Parkin, LRRK-2, Alpha-Synuclein
Honors and Awards
Montana State University, Phi Kappa Phi, 1980.
Montana State University, Student Orientation Leader Traineeship, 1980-1981.
Montana State University, Alpha Epsilon Delta, Charter President, 1981.
Montana State University, Advanced Honor Scholarship,1978-1981.
University of Utah, Summer Research Fellowship, 1982.
University of Wyoming, College of Human Medicine - Summer Preceptorship, 1982.
Epilepsy Foundation - Medical Student Research Fellowship, 1984.
University of Utah, Neuroscience Program Tuition Waiver, 1984-1985.
Pharmaceutical Manufacturing Association - Medical Student Research Fellowship, 1984-1985.
University of Utah, Summer Research Fellowship, 1985.
Dr. James A. Bush Memorial Research Award, University of Utah School of Medicine 1985 .
Hoffmann-LaRoche Graduate Student Travel Award, ASPET, 1985.
National Institute of Health, Medical Student Elective in Medical-Surgical Neurology, 1985.
American Federation for Clinical Research: Neuroscience Subspecialty Award, 1985.
Upjohn Achievement Award. Outstanding Research Contribution for the Graduating Class, University of Utah School of Medicine
The Merck Manual Award, University of Utah School of Medicine 1986.
Winter Conference on Brain Research Fellowship Award, 1990.
Pfizer Postdoctoral Fellowship Award, 1990-1992.
Dana Foundation Postdoctoral Fellowship Award, 1990-1992.
The French Foundation for Alzheimer Research Postdoctoral Fellowship Award, 1990-1992.
American Academy of Neurology Research Fellowship Award, 1990-1993.
CIDA, National Institute of Neurological Disorders and Stroke, NS-01578, 1992-1997
Ruth Salta Junior Investigator Achievement Award, for Outstanding Contribution in Alzheimer’s Disease Research, 1995
The American Academy of Neurology Decade of the Brain, Plenary Session Presentation, 1995
The Paul Beeson Physician Faculty Scholars in Aging Research Program, 1995-1998
Derek Denny-Brown Young Neurological Scholar Award, American Neurological Association, 1996
International Life Sciences Institute Award, 1994-1997
Established Investigator-American Heart Association, 1997-2001
The Ralph Rossen Memorial Lecture, 1997
The Paul Stark Lecture, Department of Pharmacology, University of Rochester, 1998
The Klayman Memorial Lecture, Department of Neurology, Washington University at Saint Louis, 1999
ISI Highly Cited Researcher Award, 2000
Santiago Grisoliá Chair and Medal, 2001
NARSAD Independent Investigator Award, 2001-2003
Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases, 2004
America’s Top Physicians Award – Neurology, Consumers Research Council of America 2004-2006.
Faculty of 1000 Biology – Neurobiology of Disease and Regeneration Section of the Neuroscience Faculty – 2006.
Huntington’s Disease Society of America – “Celebration of Hope – Distinguished Clinician Award – 2006.
Gabriele Zu Rhein Lectureship in Neuropathology, University of Wisconsin at Madison, 2006
Selected Publications
1. Liberatore, G.T., V. Jackson-Lewis, A.S. Mandir, G. McAuliffe, M. Vila, V.L. Dawson, T.M. Dawson, S. Przedborski. “Role of Inducible Nitric Oxide Synthase in Dopaminergic Neurodegeneration Caused by the Parkinsonian Toxin MPTP. Nature Medicine, 5:1403-1409, (1999).
2. Dawson, T.M. "New Animal Models for Parkinson's Disease." Cell, 101: 115-118 (2000).
3. Zhang, Y., J. Gao, K.K.K. Chung, H. Huang, V.L. Dawson and T.M. Dawson. "Parkin Functions as an E2-Dependent Ubiquitin-Protein Ligase and Promotes the Degradtion of the Synaptic Vesicle Associated Protein, CDCrel-1." Proc. Natl. Acad. Sci., U.S.A., 97:13354-13359 (2000).
4. 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).
5. Nucifora, F.C. Jr., M. Sasaki, M. F. Peters, H. Huang, J.K. Cooper, M. Yamada, H. Takahashi, H. Tsuji, J. Troncoso, V. L. Dawson, T.M. Dawson*, and C. A. Ross*. "Interference by Huntingtin and Atrophin-1 CBP-Mediated Transcription Leading to Cellular Toxicity." Science, 291: 2423-2428 (2001).
6. 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).
7. Dawson, T.M., A.S. Mandir, M.K. Lee, “Animal Models of PD: Pieces of the Same Puzzle.” Neuron, 35:219-222 (2002).
8. Lee, M.K., W. Stirling, Y. Xu, X, Xu, D. Qui, A.S. Mandir, T.M. Dawson, N.G. Copeland, N.A Jenkins, D.L. Price. “Human a-Synuclein Harboring Familial Parkinson’s Disease Linked Ala53Thr Mutation Causes Neurodegenerative Disease with a-Synuclein Aggregation in Transgenic Mice.” Proc. Natl. Acad. Sci. U.S.A., 99: 8968-8973 (2002).
9. Dawson, T.M. and V.L. Dawson. “Neuroprotective and Neurorestorative Strategies for Parkinson’s Disease.” Nature Neuroscience, 5:1058-1061 (2002).
10. Dawson, T.M. and V.L. Dawson. “Rare Genetic Mutations Shed Light on the Pathogenesis of Parkinson’s Disease.” Journal of Clinical Investigation, 111:145-51 (2003).
11. Dawson, T.M. and V.L. Dawson. “Molecular Pathways of Neurodegeneration in Parkinson’s Disease” Science, 302: 819-822 (2003).
12. 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)
13. 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).
14. Ko,, H.S., R. von Coelln, S. R. Sriram, S.W. Kim, K.K.K. Chung, B. Johnson, O. Pletnikova, E.L. Goh, H. Song, B.J. Park, M.J. Kim, S.H. Kim, V.L. Dawson, and T.M. Dawson “Accumulation of the Authentic Parkin Substrate, Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death” J. Neurosci., 25:7968-7978 (2005).
15. Lim, K.L., K.C.M. Chew, J.M.M. Tan, C. Wang, K.K.K. Chung, Y. Zhang, Y. Tanaka4*, W.L. Smith, S. Engelender, C.A. Ross, V.L. Dawson, T.M. Dawson. “Parkin mediates non-classical, proteasomal-independent, ubiquitination of Synphilin-1: Implications for Lewy Body Formation.” J. Neuroscience, 25: 2002-2009 (2005).
16. Li, W., N. West, E. Colla, O. Pletnikova, J.C. Troncoso, L. Marsh, T.M. Dawson, P. Jakala, T. Hartmann, D.L. Price and M.K. Lee. “Aggregation promoting C-terminal truncation of a-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations”. Proc. Natl. Acad. Sci. U.S.A., 102:2162-2167 (2005).
17. Moore, D.J., A.B. West, V.L. Dawson and T.M. Dawson. “Molecular Pathophysiology of Parkinson’s Disease.” Annual Review of Neuroscience, 28: 55-84 (2005).
18. West, A., D. Moore, A. Bugayenko, S. Biskup, W.W. Smith, C.A. Ross, V. L. Dawson and T.M. Dawson. “ Parkinson’s Disease Associated Mutations in Leucine Rich Repeat Kinase 2 Augment Kinase Activity.” Proc. Natl. Acad. Sci. U.S.A., 102:16842-16847 (2005).
19. Smith, W.W., Z. Pei, H. Jiang, D.J. Moore, Y. Liang, A.B. West, V.L. Dawson, T.M. Dawson and C.A. Ross. “Leucine-rich repeard kinase 2 (LRRK2) interacts with parkin and mutant LRRK2 induces neuronal degeneration.” Proc. Natl. Acad. Sci. U.S.A. 102:18,676-18,681 (2005).
20. Riccio, A., R.S. Alvania, B.E. Lonze, N. Ramanan, T. Kim, Y. Huang, T.M. Dawson, S.H. Synder and D.D. Ginty. “A Nitric Oxide Signalling Pathway Controls CREB-mediated Gene Expression in Neurons.” Molecular Cell, 21:283-294 (2006).
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