Aaron DiAntonio, MD, PhD
Alan A and Edith L Wolff Professor of Developmental Biology
- Phone: 314-362-9925
- Email: diantonio@nospam.wustl.edu
Research interests
Our laboratory investigates molecular mechanisms that control the structure and function of neural circuits in health and disease. We combine genetic, molecular, neuroanatomical, and bioinformatic analyses to identify pathways that promote the maintenance of axons and synapses in neurodegenerative disease and aging. Our prior mechanistic insights have led to the development of a novel therapeutic currently in clinical trials. Our studies focus on three major areas:
Axon Degeneration: Defining Mechanisms and Developing Therapies
Axon loss drives morbidity and progression of many common neurological diseases including peripheral neuropathy, glaucoma, traumatic brain injury, multiple sclerosis, and neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease, and ALS.
Axon degeneration is a genetically-encoded program of subcellular self-destruction. We use Drosophila, mice, and human iPSC-derived neurons to define the molecular mechanisms of the axon degeneration pathway.
We identified SARM1 as the central executioner of the axonal degeneration program and demonstrated that it is the founding member of an ancient class of enzymes that cleave the essential metabolite NAD.
Using these mechanistic insights, we have developed small molecule inhibitors and gene therapy approaches to block the SARM1 pathway that are currently in clinical development as potential therapies for neurodegenerative disease.
Neuroimmunology and Axon Glia Interactions
A comprehensive understanding of axon maintenance in health and disease requires dissecting the interactions between axons and the cellular components of the nerve such as glia, immune cells, and likely additional cell types including specialized fibroblasts and adipocytes. Our studies of neurodegeneration have highlighted the complex interplay among these cell types in the degenerative process.
We incorporate the latest single cell and spatial transcriptomic techniques with traditional genetic, metabolic, imaging, and pathological analysis to dissect the multicellular interactions within the nerve. We expect that insights will lead to the development of novel therapies targeting this cellular crosstalk.
The TIR domain: A Novel Family of NAD Cleaving enzymes
TIR domain proteins are an ancient family of NAD cleaving enzymes important for the intersection of metabolism, inflammation, and neurodegeneration.
The TIR domain is the canonical protein motif of innate immune signaling, previously defined only as a scaffold for organizing signal transduction cascades. Through our studies of SARM1, we discovered that the TIR domain is an enzyme that cleaves the essential metabolic co-factor NAD. We discovered that this ancient function of TIR domains is conserved in animals, plants, bacteria, and archaebacteria, thereby redefining our understanding of innate immune signaling across the domains of life.
We are exploring the role of TIR domain enzymes as central nodes for the integration of immune signaling, metabolism, and inflammation in neurodegenerative disease.
Seated: Xiaolu Sun, Shweta Tendulkar, Lily Spatz, Kelsey Krus
Education and Training
Professor of Department of Developmental Biology, Washington University School of Medicine, 2010-present
Associate Professor Department of Developmental Biology, Washington University School of Medicine, 2005-present
Assistant Professor Department of Developmental Biology, Washington University School of Medicine, 1999-2005
Postdoctoral Fellow University of California at Berkeley, Department of Molecular and Cell Biology, 1995-1999. Postdoctoral Advisor: Dr. Corey Goodman
Ph.D. Stanford University School of Medicine, Department of Molecular and Cellular Physiology, 1989-1995. Thesis Advisor: Dr. Thomas Schwarz
M.D. Stanford University School of Medicine, 1989-1995
M. Phil. Cambridge University, Biochemistry, 1989
A.B. Harvard University, Biochemistry and Molecular Biology, 1984-1988
Honors and Awards
Spirit of Hope Award, Hope Happens, 2023
Chancellor’s Award for Innovation and Entrepreneurship, Washington University, 2021
AAAS Fellow, American Academy for the Advancement of Science, 2020
Javits Neuroscience Award, NIH, 2020
Alan A. and Edith L. Wolff Professor of Developmental Biology, 2014
Outstanding Faculty Mentor Award, Graduate Senate, Washington University, 2011
Outstanding Faculty Mentor Award, Postdoctoral Society, Washington University, 2008
Keck Distinguished Young Scholar, 2002-2007
McKnight Scholar Award, 2002-2004
Sloan Research Fellow, 2001-2003
Edward Mallinckrodt, Jr. Foundation Award, 2000-2003
Whitehall Foundation Award, 2000-2003
Burroughs Wellcome Career Award in the Biomedical Sciences, 1998-2003
Helen Hay Whitney Fellow 1996-1998
Damon Runyon-Walter Winchell Fellow, 1996
Hershel Smith Harvard Scholarship, Harvard College, 1988
Phi Beta Kappa, Harvard College, 1988
Selected recent publications: DiAntonio Lab
- Dingwall, C.B., Strickland, A., Yum, S.W., Yim, A.K., Zhu, J., Wang P.L., Yamada, Y., Schmidt, R.E., Sasaki, Y., Bloom, A.J., DiAntonio, A., and Milbrandt, J. (2022) Macrophage depletion blocks congenital SARM1-dependent neuropathy. Journal of Clinical Investigation 132: e159800.
- Sato-Yamada, Y., Strickland, A., Sasaki, Y., Bloom, A.J., DiAntonio, A., and Milbrandt, J. (2022) A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model. Journal of Clinical Investigation 132: e161566.
- Krus, K.L., Strickland, A., Yamada, Y., Devault, L., Schmidt, R.E., Bloom, A.J., Milbrandt, J., and DiAntonio, A. (2022) Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy. Cell Reports, 111001.
- Bloom, A.J., Mao, X., Strickland, A., Sasaki, Y., Milbrandt, J., and DiAntonio, A. (2022) Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients. Molecular Neurodegeneration 17-1.
- Ko, K.W., Devault, L., Sasaki, Y., Milbrandt, J., and DiAntonio, A. (2021) Live imaging reveals the cellular events downstream of SARM1 activation. Elife 10: e71148.
- Figley M.D., Gu W., Nanson J.D., Shi Y., Sasaki Y., Cunnea K,. Malde A.K., Jia X., Luo Z., Saikot F.K., Mosaiab T., Masic V., Holt S., Hartley-Tassell L,. McGuinness H.Y., Manik M.K., Bosanac T., Landsberg M.J., Kerry P.S., Mobli M., Hughes R.O., Milbrandt J., Kobe B., DiAntonio A., Ve T. (2021) SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron 109: 1118-1136.
- Ko, K.W., Milbrandt, J., and DiAntonio, A. (2020) SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration. Journal of Cell Biology 219: e201912047.
- Wan, L., Essuman, K., Anderson, R.G., Sasaki, Y., Monteiro, F., Chung, E., Nishimura, E.O., DiAntonio, A., Milbrandt, J., Dangl, J.L., and Nishimura, M.T. (2019) TIR Domains of Plant Immune Receptors are NAD+ Cleaving Enzymes that Promote Cell Death. Science 365: 799-803.
- Geisler, S., Huang, S., Strickland, A., Doan, R.A., Summers, D.W., Mao, X., DiAntonio, A., and Milbrandt, J. (2019) Gene therapy targeting SARM1 blocks pathological axon degeneration in mice. Journal of Experimental Medicine 216: 294-303.
- Summers, D.W., Milbrandt, J., and DiAntonio, A. (2018) Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. P.N.A.S. 115: E8746-E8754. PMC6140512
- Essuman, K., Summers, D.W., Sasaki, Y., Mao X., Yim A.K.Y., DiAntonio, A., Milbrandt, J. (2018) TIR Domain Proteins Are an Ancient Family of NAD+ Consuming Enzymes. Current Biology 28: 421-430.
- Essuman, K., Summers, D.W., Sasaki, Y., Mao, X., DiAntonio, A., Milbrandt, J. (2017) The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axon Degeneration. Neuron 93: 1334-1343.
- Walker, L.J., Summers, D.W., Sasaki, Y., Brace, E.J., Milbrandt, J., and DiAntonio, A. (2017) MAPK Signaling Promotes Axonal Degeneration by Speeding the Turnover of the Axonal Maintenance Factor NMNAT2. eLife 2017; 6:e22540.
- Gerdts, J., Brace, E.J., Sasaki, Y., DiAntonio, A., and Milbrandt, J. (2015) Sarm1 activation triggers axon degeneration locally via NAD+ destruction. Science 348: 453-7.