The long-term goal of this proposal is to define the molecular mechanisms that promote axonal degeneration following injury or disease. Axonal degeneration is a common feature of many neurological diseases. Neuropathies due to axonal degeneration are a hallmark of disorders such as diabetes, glaucoma, and chemotherapy-induced neurotoxicity and axonal loss is an early feature of debilitating neurodegenerative diseases. The great length of many axons makes them particularly vulnerable to mechanical injury, and axonal degeneration following trauma is a major cause of disability. Recent studies demonstrate that axonal degeneration is an active and highly regulated process, yet the intrinsic, neuronal mechanism promoting degeneration is poorly understood. This proposal investigates what causes axons to degenerate, and how this can be prevented. 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. It proceeds as a stepwise process that begins with microtubule destabilization, followed by rapid blebbing of the axonal membrane, axonal fragmentation, cytoskeletal degradation and eventual engulfment by glial and/or phagocytic cells. We now demonstrate that the DLK pathway functions in the intrinsic neuronal pathway that promotes axonal degeneration following injury. Identifying and characterizing the function of components of the intrinsic axonal degeneration pathway will provide insights into its mechanism as well as potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.

Public Health Relevance

This research is relevant to public health because it will improve our understanding of the mechanism of axonal degeneration following injury and disease. Axonal degeneration is a prominent component of many neurological disorders including neuropathies associated with trauma, diabetes, glaucoma, chemotherapy-induced neurotoxicity, and neurodegenerative diseases. Identifying components of the pathway in axons that promote degeneration will provide insights into the fundamental mechanism underlying axonal degeneration as well as potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Jakeman, Lyn B
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Washington University
Other Basic Sciences
Schools of Medicine
Saint Louis
United States
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Summers, Daniel W; Milbrandt, Jeffrey; DiAntonio, Aaron (2018) Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. Proc Natl Acad Sci U S A 115:E8746-E8754
Karney-Grobe, Scott; Russo, Alexandra; Frey, Erin et al. (2018) HSP90 is a chaperone for DLK and is required for axon injury signaling. Proc Natl Acad Sci U S A 115:E9899-E9908
Essuman, Kow; Summers, Daniel W; Sasaki, Yo et al. (2017) The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron 93:1334-1343.e5
Walker, Lauren J; Summers, Daniel W; Sasaki, Yo et al. (2017) MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2. Elife 6:
Brace, E J; DiAntonio, Aaron (2017) Models of axon regeneration in Drosophila. Exp Neurol 287:310-317
Summers, Daniel W; Gibson, Daniel A; DiAntonio, Aaron et al. (2016) SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci U S A 113:E6271-E6280
Gerdts, Josiah; Summers, Daniel W; Milbrandt, Jeffrey et al. (2016) Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron 89:449-60
Hao, Yan; Frey, Erin; Yoon, Choya et al. (2016) An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK. Elife 5:
Bhattacharya, Martha R C; Geisler, Stefanie; Pittman, Sara K et al. (2016) TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance. J Neurosci 36:4681-9
Sasaki, Yo; Nakagawa, Takashi; Mao, Xianrong et al. (2016) NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion. Elife 5:

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