Aaron DiAntonio, M.D., Ph.D.

Developmental Biology

Neurosciences Program
Developmental, Regenerative and Stem Cell Biology Program

  • 314-362-9925

  • 314-362-9866

  • 314-362-7058

  • 4515 McKinley Avenue, 6th floor

  • diantonio@wustl.edu

  • https://diantoniolab.wustl.edu/

  • axon regeneration, axon degeneration, neurodegeneration, glia, neuronal development and differentiation, neuroinflammation, neuroimmunology, synapse biology, drug screens, metabolism

  • Neural circuits in development and disease

Research Abstract:

Our laboratory investigates molecular mechanisms that control the structure and function of neural circuits in development and disease. We combine genetic, molecular, neuroanatomical, and electrophysiological studies in both Drosophila and mouse to identify pathways required for the development, maintenance, and regeneration of axons and synapses. Our studies focus on four major areas:

1) Axonal degeneration in disease: Axonal degeneration is a common feature of many neurological diseases including hereditary neuropathies, diabetes, glaucoma, chemotherapy-induced neurotoxicity, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Axonal degeneration is an active process of self-destruction that appears to be naturally primed and waiting for a triggering stimulus that activates the execution phase. We identified the DLK/JNK MAP kinase pathway as the first intrinsic neuronal pathway that promotes axonal degeneration following injury. Using genome-wide screens in both Drosophila and mice we identified SARM1 as the central executioner of the axonal degeneration program and are defining its molecular activities. These mechanistic insights have identified potential therapeutic targets that we are testing in neurological disease models characterized by axonal degeneration.

2) Axonal regeneration in response to injury: Neuronal repair is greatly impaired by the failure of adult CNS neurons to regenerate axons lost to injury or disease. Remarkably, a prior preconditioning injury can activate an axonal growth program and promote axonal regeneration. We have recently demonstrated that the MAPKKK DLK is a key trigger that induces this preconditioning response. We are investigating the mechanisms by which this regenerative growth program can be activated in order to promote neuronal repair. Finally, we are using high-content automated screening approaches to undertake large-scale drug and RNAi screens in order to identify novel therapeutic candidates that induce axonal regeneration.

3) Neuroimmunology: The TIR domain is the signature protein motif of innate immune signaling and is well studied as a scaffold to promote signal transduction. We have recently discovered that the primordial function of the TIR domain is to act as an enzyme that cleaves the essential metabolic co-factor NAD. This function of TIR domains is conserved in animals, plants, bacteria, and archebacteria, motivating a re-evaluation of the mechanisms of innate immune signaling throughout the domains of life. In particular, we have demonstrated that this enzymatic function of TIR domains is central to the neuronal response to injury. We are now pursuing projects to explore the role of enzymatic TIR function in neuroimmune signaling in order to dissect the mechanisms that link metabolism, inflammation, and neurodegeneration.

4) Synaptic and axonal physiology: We investigate molecular mechanisms that control synaptic strength and axonal excitability. In this work we are exploring key functional targets of FMRP in models of Fragile X syndrome to identify pharmacological and genetic tools to ameliorate synaptic dysfunction in this disorder. We also explore the role of glial cells in maintaining healthy and functional axons and are currently defining signaling pathways in the glia that are essential for proper axonal physiology.

Selected Publications:

Summers, D.W., Milbrandt, J., DiAntonio, A. (2018) Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. PNAS 115(37):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. PMC5802418

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. PMC5241118

Gerdts, J., Summers, D.W., Milbrandt, J., and DiAntonio, A. (2016) Axon self-destruction: new links among SARM1, MAPKs, and NAD+ metabolism. Neuron 89: 449-460. PMC4742785

Geisler, S., Doan, R.A., Strickland, A., Huang, X., Milbrandt, J., and DiAntonio, A. (2016) Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain 139: 3092-3108.

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. PMC4513950.

Shin, J.E., Cho, Y., Beirowski, B., Milbrandt, J., Cavalli, V., and DiAntonio, A. (2012) Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron 74: 1015-1022 PMCID: PMC3383631

Graf ER, Daniels RW, Burgess RW, Schwarz T and DiAntonio A. Rab3 Dynamically Controls Protein Composition at Active Zones. Neuron 2009 64: 663-677. PMCID: PMC2796257

Miller RB, Press C, Daniels RW, Sasaki Y, Milbrandt J and DiAntonio A. A DLK-dependent axon self-destruction program promotes Wallerian degeneration. Nature Neuroscience 2009 12: 387-389. PMCID: PMC2696160

Last Updated: 10/22/2018 8:06:18 AM

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