Dr. Ted Dawson, MD, PhD
Johns Hopkins University
- Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases, Johns Hopkins University
- Scientific Director, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Co-Director, Neuroregeneration Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine
Dr. Dawson is collaborating with AGT to develop a gene therapeutic to arrest the development of Parkinson’s disease (PD) and other neurological disorders.
The main focus of the Dawson Laboratory at Johns Hopkins University is to unravel the molecular basis of neurodegeneration, which parallels Dr. Dawson’s clinical interest in neurodegenerative diseases.
The laboratory uses genetic, cell biological and biochemical approaches to explore the pathogenesis of Parkinson’s disease (PD) and other neurologic disorders. They also investigate several discrete mechanisms involved in cell death, including the role of nitric oxide as an endogenous messenger, the function of poly (ADP-ribose) polymerase-1 and apoptosis inducing factor in cell death, and how endogenous cell survival mechanisms protect neurons from death.
There are five broad areas of investigation:
- The study of the mechanisms of neuronal cell death;
- Nitric oxide (NO) signaling ;
- The study of novel cell death and cell survival pathways;
- The study of the molecular basis of Parkinson’s disease;
- Testing innovative neuroprotective and neurorestorative strategies in PD patients.
Dr. Dawson and his team originally identified NO as a major player in neuronal cell death, and they are investigating NO-death and NO-survival signaling pathways. They have shown that poly (ADP-ribose) polymerase (PARP) is a major target of NO-mediated neuronal injury and that selective inhibitors or knockout of PARP are profoundly neuroprotective in animal models of stroke and PD.
They 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. The team is also investigating the mechanism by which PARP activation triggers AIF release and AIF kills cells.
PD is a common disorder of the nervous system that afflicts patients later in life with tremor, slowness of movement, gait instability, and rigidity. Loss of dopamine neurons accounts for the major signs and symptoms of PD, and mutations in at least five genes including a-synuclein, parkin, PINK1, DJ-1 and LRRK2 are responsible for rare Mendelian forms of PD. In addition to the progressive loss of dopamine neurons, PD is characterized by neurodegeneration throughout the central nervous system and by the accumulation of a-synuclein and other proteins in structures called Lewy bodies and Lewy neurites. Despite genetic advances in our understanding of PD, it is primarily considered a sporadic disorder with no known cause. Current evidence suggests that mitochondrial complex I abnormalities may be one of the major contributors to sporadic PD. Much as the discovery of dopamine deficiency led to potent treatments for motor symptoms, we believe that recent discoveries concerning the role of specific genes in Parkinson disease pathology will lead to the next revolution in disease therapy. Accordingly, the role of these genes in the pathogenesis of PD; and how mitochondrial complex I deficiency potentially leads to pathologic derangements in the function of these proteins has become a major focus of the Dawson Laboratory.
The team is 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. The team found that parkin is an ubiquitin E3 protein ligase and that disease-causing mutations inhibit its E3 activity. They 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. The team discovered that S-nitrosylation of parkin impairs its function. This discovery 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, the team has knocked out DJ-1, PINK1, LRRK2 and parkin, and they are identifying and characterizing protein targets of parkin and the biologic function of LRRK2, DJ-1 and PINK1.
They are interested in genes essential for cell survival. To this end, they have been studying the role of NO as a survival molecule. Taking advantage of their findings that NO plays an important role in activity-dependent neuroprotection, they focused on identifying genes that are regulated by NO’s activation of Ras, and more than 30 candidate neuroprotective genes have been identified. Understanding the mechanism by which these proteins regulate neuronal survival may lead to the identification of innovative therapies for the treatment of neurologic disorders.
- Andrabi SA, Umanah GK, Chang C, Stevens DA, Karuppagounder SS, Gagné JP, Poirier GG, Dawson VL, Dawson TM. Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A.2014 Jul 15;111(28):10209-14. doi: 10.1073/pnas.1405158111. Epub 2014 Jul 1. PMID: 24987120
- Sagal J, Zhan X, Xu J, Tilghman J, Karuppagounder SS, Chen L, Dawson VL, Dawson TM, Laterra J, Ying M. Proneural transcription factor atoh1 drives highly efficient differentiation of human pluripotent stem cells into dopaminergic neurons. Stem Cells Transl Med. 2014 Aug;3(8):888-98. doi: 10.5966/sctm.2013-0213. Epub 2014 Jun 5. PMID: 24904172
- Chen YC, Umanah GK, Dephoure N, Andrabi SA, Gygi SP, Dawson TM, Dawson VL, Rutter J. Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. EMBO J. 2014 Jul 17;33(14):1548-64. doi: 10.15252/embj.201487943. Epub 2014 May 19. PMID: 24843043 [PubMed – in process]
- Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease. Sci Rep. 2014 May 2;4:4874. doi: 10.1038/srep04874. PMID: 24786396 [PubMed – in process]
- Chi Z, Byrne ST, Dolinko A, Harraz MM, Kim MS, Umanah G, Zhong J, Chen R, Zhang J, Xu J, Chen L, Pandey A, Dawson TM, Dawson VL. Botch is a γ-glutamyl cyclotransferase that deglycinates and antagonizes Notch. Cell Rep. 2014 May 8;7(3):681-8. doi: 10.1016/j.celrep.2014.03.048. Epub 2014 Apr 24. PMID: 24767995
- 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).