Research Summary
Molecular Mechanisms of Neurodegeneration, Neuronal Signaling
and Neuronal Cell Death
 The
main focus of my laboratory is to unravel the molecular basis of neurodegeneration,
which parallels my clinical interest in neurodegenerative diseases. My laboratory
collaborates closely with Dr. Valina L Dawson. 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. As an
illustration of our bench to bedside approach of our research, Johns Hopkins
patented this discovery and licensed it to Guilford Pharmaceuticals. Guilford
and other pharmaceutical companies are developing selective PARP inhibitors
for the treatment of a variety of human disorders. Inotek Pharmaceuticals is
currently in phase II trials with a selective PARP inhibitor. 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, including Endo
G. We are also investigating the mechanism by which PARP activation triggers
AIF release with the hope of identifying novel signaling pathways that might
be amenable to therapeutic intervention.
We identified the neuroprotective and equally important, neuroregenerative
properties of the neuroimmunophilins. Our group was instrumental in defining
the key chemical structure for a novel class of compounds, the non-immunosuppressive
immunophilins, which are profoundly neuroprotective and neuroregenerative.
These studies formed the basis for the development of a novel potent series
of neuroimmunophilin agents that have nerve regenerative properties with profound
clinical implications. However, the mechanism by which they promote neuronal
survival and regeneration is not known. Studies are underway to better understand
their mechanism of action, which may yield better therapeutics.
We identified NO as an activator of the Ras-cell survival signaling
pathway and we are currently identifying the genes that are induced by activation
of this pathway using novel gene identification strategies and microarray analysis
developed in our laboratory. We have identified several novel genes that are
profoundly neuroprotective against a variety of insults and we are in the process
of characterizing these gene products. Elucidation of the mechanism by which
these gene products enhance neuronal survival may provide innovative targets
for the treatment of neurologic disease.
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 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 and parkin and we are identifying and characterizing protein targets
of parkin and the biologic function of DJ-1 and PINK1. To access the role of
a-synuclein in PD we have created a-synuclein transgenic mice and we have identified
novel post-translational modifications that appear to influence the toxicity
of a-synuclein. Identification of the enzymes responsible for post-translational
modification of a-synuclein may provide innovative therapeutic targets for
the treatment of PD.
Graduate Programs
Cellular and
Molecular Medicine
Neuroscience
Representative Publications
 eBriefing: Neurodegenerative
Diseases: From Mechanism to Medicine
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).
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).
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).
Dawson, T.M. and V.L. Dawson. “Neuroprotective and Neurorestorative
Strategies for Parkinson’s Disease.” Nature Neuroscience, 5:1058-1061
(2002).
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., A.S. Mandir and M.K. Lee, “Animal Models of PD; Pieces
of the Same Puzzle.” Neuron, 35: 219-222 (2002).
Dawson, T.M. and V.L. Dawson. “Molecular Pathways of Neurodegeneration
in Parkinson’s Disease” Science, 302: 819-822 (2003)
Li, H., X. Gu, V.L. Dawson and T.M. Dawson. “Identification of Calcium
and Nitric Oxide Regulated Genes by Differential Analysis of Library Expression
(DAzLE). Proc. Natl. Acad. Sci. U.S.A., 101: 647-652 (2004).
Hong, S.J., H. Li, K.G. Becker, V.L. Dawson*, and T.M. Dawson*. “Identification
and Analysis of Plasticity-Induced Late Response Genes.” Proc. Natl.
Acad. Sci. U.S.A., 101:2145-2150 (2004).
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).
Hong, S.J., T.M. Dawson and V.L. Dawson. “Nuclear and Mitochondrial
Conversations in Cell Death: PARP-1 and AIF Signaling.” Trends in Pharmacological
Sciences, 25: 259-264 (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).
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