Welcome to the Dawson Lab
We are part of the Institute for Cell Engineering Neuroregeneration Program and Stem Cell Programs. Our research is focused on the molecular basis for neurodegeneration, neuronal cell death, and survival.
The Dawson lab studies neuronal cell death and survival, the molecular underpinnings of Parkinson’s disease (PD), stroke and related disorders.
The lab identified a regulated cell death program, called Parthanatos. In the brain, Parthanatos is important in ischemic and excitotoxic injury, as well as PD. Parthanatos, builds upon earlier work where the lab was first to show that nitric oxide (NO) is a key mediator of glutamate neurotoxicity. The cell death mechanism involves nuclear activation of poly(ADP-ribose) polymerase and mitochondrial release of apoptosis inducing factor, which recruits macrophage migration inhibitory factor (MIF) that co-translocate to the nucleus. Once in the nucleus, MIF, a DNA nuclease, cleaves genomic DNA and functions as the executioner in Parthanatos. The laboratory identified the first in class, MIF nuclease inhibitor that is profoundly protective in three orthogonal animal models of PD. Current research aims to further understand how this pathway works.
The Dawson lab has also been at the forefront of research into the biology and pathobiology of the proteins and mutant proteins linked to Parkinson’s disease. It showed that parkin is a ubiquitin E3-ligase, which is inactivated due to parkin mutations. The lab identified three parkin substrates, PARIS (ZNF746), AIMP2, and NLRP3 that accumulate in PD and drive the loss of dopamine neurons in experimental models. It discovered that nitric oxide (NO)-mediated S-nitrosylation or c-Abl mediated tyrosine phosphorylation of parkin inactivates parkin in sporadic PD, spurring the development of therapeutic parkin activators. The lab also showed that c-Abl is overactive in PD and that interfering with c-Abl activity prevents neurodegeneration in PD models leading to clinical trials of c-Abl inhibitors. The lab showed that DJ-1 is an atypical peroxidoxin-like peroxidase and that its absence in PD leads to mitochondrial dysfunction. Our laboratory was the first to show that disease-causing mutations in LRRK2 enhanced its kinase activity and linked the enhanced kinase activity to neurodegeneration. We also identified the first round of LRRK2 kinase inhibitors that were neuroprotective in models of PD leading to the advancement of LRRK2 inhibitors as disease-modifying agents in PD. We showed that mutations in LRRK2 cause PD through pathologic kinase activity leading to enhanced protein translation via the phosphorylation of the ribosomal protein s15 and that inhibiting LRRK2 is protective. In collaborative studies, the lab also showed that dysregulated phosphorylation of the Rab GTPases, including Rab 35 contribute to LRRK2 induced neurodegeneration. The laboratory discovered that pathologic a-synuclein spreads in the nervous system via engagement with the lymphocyte-activation gene 3 (LAG3). In collaborative studies, the laboratory showed that neurotoxic reactive astrocytes contribute to neurodegeneration in PD and other neurodegenerative diseases. Our laboratory co-developed NLY01, a brain-penetrant GLP1 receptor agonist, that is neuroprotective by preventing microglial and neurotoxic reactive astrocyte activation. NLY01 is currently under evaluation as a disease-modifying agent in PD. The laboratory is building on these studies and investigating the role of innate and adaptive immunity in PD. Collectively, our studies provide major insights into understanding the pathogenesis of PD and stroke and provide novel opportunities for therapies aimed at preventing the degenerative process of PD and other neurologic disorders.
In addition to cell death, the team strives to understand how cells survive by characterizing survival genes and proteins involved in neuronal resilience. The team uses induced pluripotent stem cells to identify genetic and pharmaceutical agents that might be used therapeutically to protect the brain.
Currently, the laboratory is focused on the following:
Cell to cell transmission of pathologic a-synuclein.
Poly(ADP-ribose) signaling and parthanatos
MIF nuclease signaling in Parkinson’s disease, Alzheimer’s disease and stroke
Adaptive and innate immunity in Parkinson’s disease, Alzheimer’s disease and stroke
cGAS, STING, and NLRP3 inflammasome signaling in neurodegenerative diseases
Microglial and Neurotoxic Astrocyte induced neurodegeneration
ZNF746 (PARIS) and related ZNFs in controlling transcriptional programs that regulate neuronal survival
Neuronal resilience
Structural biology using Cryo-EM to understand structure activity relationships of MIF nuclease, Thorase (ATAD1) and ZNF746
Characterization of pathologic a-synuclein strains and mechanism of neurodegeneration
PRINCIPAL INVESTIGATORS
Ted M. Dawson, MD, PhD
TITLES
Director, Institute for Cell Engineering
Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases
Professor of Neurology, Neuroscience, Pharmacology, and Molecular Sciences
BACKGROUND
Dr. Dawson has dedicated his career to deciphering the mechanisms that control neurodegeneration and neuronal cell death. Dawson attended Montana State University and received a B.S. in Premedicine in 1981 with highest honors. He received a M.D. and Ph.D. in Pharmacology in 1986 from the University of Utah where he also completed an Internship in Internal Medicine. At the Hospital of the University of Pennsylvania, he completed a Neurology Residency in 1990. After postdoctoral training with Solomon H. Snyder and a clinical movement disorder fellowship at Johns Hopkins University School of Medicine, he joined the Departments of Neurology and Neuroscience in 1994 and became Professor in 2000. From 1996 to 2010 he was director of the Parkinson’s Disease and Movement Disorder Center. He co-founded the Neuroregeneration Program in the Institute for Cell Engineering in 2002 and became the Scientific Director of the Institute for Cell Engineering in 2010 and its Executive Director in 2011. He is currently the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and Director of the Institute for Cell Engineering.
Dawson’s honors include the Derek Denny-Brown Young Neurological Scholar Award from the American Neurological Association, the Paul Beeson Physician Faculty Scholar Award, the Santiago Grisolia Medal Santiago Grisolia Medal, Thomson Reuters Highly Cited Researcher Award(s) and Worlds’ Most Influential Scientific Minds and the Javits Neuroscience Investigator Award. He was elected to the Association of American Physicians and is a Fellow of the American Association for the Advancement of Science, American Academy of Neurology, the American Heart Association, and the National Academy of Inventors. He is a member of the National Academy of Medicine. He has served and serves on foundations, editorial boards, and professional societies.
Dr. Dawson studies of nitric oxide (NO) led to major insights into the neurotransmitter functions of this gaseous messenger molecule. He pioneered the role of NO in neuronal injury in Parkinson’s disease, stroke, and excitotoxicity. He showed that NO derived from neuronal NO synthase and immunologic NO synthase leads to degeneration of dopamine neurons through cell autonomous and non-cell autonomous affects, respectively. Dawson elucidated the molecular mechanisms by which NO kills neurons through the actions of poly (ADP-ribose) (PAR) polymerase (PARP) and discovered a unique cell death pathway designated parthanatos, in which PAR functions as an intracellular signaling molecule that induces the release of apoptosis inducing factor (AIF) causing cell death via the recruitment of the nuclease, macrophage migration inhibitory factor (MIF). Dawson identified the first in class MIF nuclease inhibitor that is protective in models of PD. He showed that poly (ADP-ribose) glycohydrolase, which degrades PAR polymer is an endogenous inhibitor of parthanatos. In screens for neuroprotective proteins, he discovered another endogenous inhibitor of parthanatos, Iduna (RNF146), a first in class PAR-dependent E3 ligase. In the same screens, he also discovered Thorase, an AAA+ ATPase that regulates glutamate (AMPA) receptor trafficking, mTor signaling, and discovered that Thorase is an important regulator of synaptic plasticity, learning and memory. Botch was also discovered as in important inhibitor of Notch signaling via deglycination of Notch preventing Notch’s intracellular processing at the level of the Golgi, playing an important role in neuronal development.
Dawson has also been at the forefront of research into the biology and pathobiology of the proteins and mutant proteins linked to Parkinson’s disease. Dr. Dawson showed that parkin is a ubiquitin E3 ligase that is inactivated in patients with genetic mutations in parkin and that it is also inactivated in sporadic Parkinson’s disease via S-nitrosylation and c-Abl tyrosine phosphorylation leading to accumulation of pathogenic substrates. He showed that c-Abl is overactive in PD and that interfering with c-Abl activity prevents neurodegeneration in PD models leading to clinical trials of c-Abl inhibitors. He discovered the parkin substrate, PARIS, which plays a key pathogenic role in PD pathogenesis by inhibiting mitochondrial biogenesis. He also showed that the parkin substrate, AIMP2 is a non-conical activator of PARP, that contributes to neurodegeneration in PD. He showed that DJ-1 is an atypical peroxidoxin-like peroxidase and that its absence in PD leads to mitochondrial dysfunction. He showed that mutations in LRRK2 cause PD through pathologic kinase activity leading to enhanced protein translation via the phosphorylation of the ribosomal protein s15 and that inhibiting LRRK2 is protective. His laboratory discovered that pathologic a-synuclein spreads in the nervous system via engagement with the lymphocyte-activation gene 3 (LAG3). In collaborative studies, Dawson showed that neurotoxic reactive astrocytes contribute to neurodegeneration in PD and other neurodegenerative disease and identified a brain penetrant GLP1 receptor agonist that is neuroprotective by preventing microglial and neurotoxic reactive astrocyte activation that is currently in clinical trials. The laboratory is building on these studies and investigating the role of innate and adaptive immunity in PD and recently showed that STING activation contributes to neurodegeneration in PD. It also showed NLRP3 is a parkin substrate leading to activation of the NLRP3 inflammasome in a PARIS dependent manner contributing to neurodegeneration in PD.
Collectively, these studies are providing major insights into understanding the pathogenesis of PD, stroke, and related neurologic disorders, providing novel opportunities for therapies aimed at preventing the degenerative process of PD and other neurologic disorders.
Valina L. Dawson, PhD
TITLES
Director, Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering
Professor of Neurology, Neuroscience, and Physiology
BACKGROUND
Dr. Dawson grew up in the Sonoma Valley Wine Country in California. Dr. Dawson received her B.S. in Environmental Toxicology in 1983 from the University of California at Davis. She earned her Ph.D. in Pharmacology and Toxicology Ph.D. degrees from the University of Utah School of Medicine. Postdoctoral training was conducted at the University of Pennsylvania and the National Institute on Drug Abuse Addiction Research Center. Dr. Dawson joined the faculty at Johns Hopkins University School of Medicine in 1994 and was promoted to Professor in 2001. In 2002 she co-founded the Neuroregeneration Program at the Institute of Cell Engineering and became Director of the Stem Cell Program in 2009. She was named a Danial Nathans Innovator in 2017. She served the Society for Neuroscience as a Reviewing Editor (2003-2009) and then as a Senior Editor (2010-2016) for the Journal of Neuroscience. She is now an Advisory Board Editor for eNeuro. She also served the Society for Neuroscience on the Committee on Women in Neuroscience, Professional Development Committee, and the Program Committee. She serves on Advisory Boards for academic programs, foundations, and pharmaceutical industries. She is an elected fellow to the National Academy of Inventors, American Heart Association (F.A.H.A.) American Association for the Advancement of Science, and American Neurological Association. She is a Clarivate Highly Cited Researcher, World’s Most Influential Minds, and Best Female Scientist Award by research.com. Notably, in the 2023 edition of Research.com's Ranking of Top 1000 Female Scientists in the World, Dr. Dawson achieved a remarkable ranking of 79 globally and 50 in the United States.
Dr. Dawson studies the molecular mechanisms that lead to neuronal cell death in neurodegenerative diseases, stroke, and trauma. She discovered the critical role that nitric oxide (NO) plays in glutamate excitotoxicity and the elevation of poly (ADP-ribose) polymer (PAR), a cell death signaling molecule, by activation of PAR polymerase (PARP). Her research team discovered that PAR leads to cell death by facilitating the release of apoptosis inducing factor (AIF) factor from the mitochondrial surface. PAR-bound AIF then recruits macrophage migration inhibitory factor (MIF), and the complex translocates to the nucleus, where the nuclease activity of MIF leads to large-scale DNA fragmentation. This cell death program was named Parthanatos for PAR and the Greek god of death, Thanatos. In genetic screens to find cell signals that prevent neurotoxicity, her team discovered an endogenous inhibitor of parthanatos, Iduna (RNF146), a first-in-class PAR-dependent E3 ligase. In the same screens, Botch was discovered as an important inhibitor of Notch signaling via deglycination of Notch, preventing Notch’s intracellular processing at the level of the Golgi, playing an important role in neuronal development and survival. Thorase, an AAA+ ATPase, regulates glutamate (AMPA) receptor trafficking and synaptic plasticity, learning and memory, and disassembly of mTORC at the lysosome. Genetic variants of Thorase were found in schizophrenic patients. Expression of these variants in mice led to behavioral deficits that were normalized with the AMPA antagonist Parampenal. Mutations in Thorase leading to gain or loss of function result in lethal developmental disorders in children.
The research team has probed the biological and pathologic actions of mutated proteins that are rare causes of Parkinson’s disease. They discovered parkin was an E3 ligase that is inactive in patients with genetic mutations in parkin. It is also inactive in sporadic Parkinson’s disease due to protein modifications by S-nitrosylation and c-Abl tyrosine phosphorylation, which led to discovering the pathogenic targets PARIS and AIMP2. Inhibitors of c-Abl are now in clinical trials. PARIS regulates the machinery critical to mitochondrial quality control and, thus, cell survival. AIMP2 directly interacts with PARP and activates Parthanatos. They discovered that DJ-1, which is dysfunctional in Parkinson’s disease, is an atypical peroxidoxin-like peroxidase and that its loss of function in PD leads to mitochondrial dysfunction. Mutations in LRRK2 increase its kinase activity, and inhibition of LRRK2 kinase activity is protective in models of Parkinson’s disease. The increased LRRK2 kinase activity leads to enhanced protein translation via the phosphorylation of the ribosomal protein s15. Collaborative studies revealed that pathologic alpha-synuclein spreads in the nervous system via engagement with the lymphocyte-activation gene 3 (LAG3) and that injection of pathologic synuclein into the gut of mice result in a mouse model of Parkinson’s disease that presents with both non-motor and motor symptoms. Their work continues to provide critical insights into the understanding of the pathogenesis of PD and identify new opportunities for therapies to treat patients with Parkinson’s disease. Neurotoxic activated astrocytes also contribute to neurodegeneration. In collaborative studies, we identified a novel glucagon-like peptide 1 (GLP1) agonist, NLY01, which is protective in models of Parkinson’s and Alzheimer’s disease and is now in clinical trials. Recently we have discovered a role for STING in neurodegeneration and activation of the NLRP3 inflammasome. New areas of investigation focus on the non-cell autonomous actions of inflammation in neurologic injury. Future studies will continue to identify the effectors of disease and develop therapies to treat these devastating diseases.
COLLABORATING LABS
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The Kam Lab
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The Kang Lab
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The Mao Lab
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The Sachdeva Lab
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The Xu Lab
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The Ko Lab