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

Professor
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.


Selected Publications:

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.

Figley, M.D. and DiAntonio, A. (2020) The SARM1 Axon Degeneration Pathway: Control of the NAD+ Metabolome Regulates Axon Survival in Health and Disease. Curr. Opin. Neurobiol. 63: 59-66.

Ko, K.W., Milbrandt, J., and DiAntonio, A. (2020) SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration. J.C.B. 219: e201912047.

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. PMC6363435

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., 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.

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.



Last Updated: 11/7/2022 11:35:25 AM

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