Aaron DiAntonio, M.D., Ph.D.
Developmental, Regenerative and Stem Cell Biology Program
333 McDonnell Medical Sciences Building
axon, endocytosis, nerve regeneration, axon degeneration, neurodegeneration, neuronal development and differentiation, synapse biology, drug screens
Neural circuits in development and disease
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 three 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. We are using genome-wide screens in both Drosophila and mice to identify the molecular mechanisms driving axonal degeneration. Identifying and characterizing components of the intrinsic axonal degeneration pathway has identified potential therapeutic targets for the many neurological diseases 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) Synaptic function: Neurotransmitter is released from the presynaptic cell at specialized sites called active zones. Efficient synaptic transmission requires that active zones contain a normal complement of proteins, and that these specialized release sites be apposed to postsynaptic clusters of neurotransmitter receptor. Little is known of the molecular mechanisms that regulate the protein composition of active zones and ensure the alignment of neurotransmitter release and reception machinery. Using large-scale genetic screens in Drosophila we are uncovering the molecular mechanisms that form and maintain the active zone/receptor cluster dyad.
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.
Valakh, V., Frey, E., Babetto, E., Walker, L.J., and DiAntonio, A. (2015) Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury. Neurobiology of Disease 77: 13-25. PMC4402261.
Summers, D.W., DiAntonio, A., and Milbrandt, J. (2014) Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. J. Neuroscience 34: 9338-9350. PMC4087211
Shin, J.E., Geisler, S., and DiAntonio, A. (2014) Dynamic regulation of SCG10 in regenerating axons after injury. Experimental Neurology 252: 1-11. PMC3947015
Babetto, E., Beirowski, B., Russler, E.V., Milbrandt, J., and DiAntonio, A. (2013) The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Reports 5: 1422-1429. PMCID: PMC3671584
Shin, J.E., Miller, B.R., Babetto, E., Cho, Y., Sasaki, Y., Qayum, S., Russler, E.V., Cavalli, V., Milbrandt, J., and DiAntonio, A. (2012) SCG10 is a JNK target in the axonal degeneration pathway. P.N.A.S. 109: E3696-3705. PMCID: PMC3535671
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
Bhattacharya M.R.C., Gerdts J., Naylor S.A., Royse E., Ebstein S.Y., Sasaki Y., Milbrandt J., and DiAntonio A. (2012) A Model of Toxic Neuropathy in Drosophila Reveals a Role for MORN4 in Promoting Axonal Degeneration. J. Neuroscience 32: 5054-5061. PMCID: PMC3336743
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: 8/13/2015 9:51:36 AM