Neuronal injury and disease are a huge burden to patients, families, and society. Improved treatments for neurological disorders will require a better understanding of how neurons respond to pathological insults in order to manipulate these responses for therapeutic benefit. Axons are a particularly vulnerable component of neural circuits that are damaged in many neurological diseases. With injury or disease, there are three primary neuronal responses to axon injury: 1) the axon may undergo a regulated self-destruction mechanism of axonal degeneration, 2) in the peripheral nervous system the neuron may activate an axonal growth program that can result in axonal regeneration, and 3) the injured neuron may die. The MAP3K Dual leucine zipper kinase (DLK) is a key regulator of each neuronal response to injury, axon degeneration, axon regeneration, and neuronal cell death. The central role of DLK in the neuronal response to injury leads to the hypothesis that DLK is a key sensor of axonal injury, transducing that signal to the remainder of the cell where it may trigger degenerative, regenerative, and apoptotic responses. While it is clear that DLK plays a seminal role in the axonal injury response pathway, numerous open questions remain that must be addressed in order to define the therapeutic potential of targeting DLK. First, how does DLK promote both regenerative and degenerative responses to injury? Understanding these mechanisms could be useful for selectively manipulating these outcomes. Second, while DLK is necessary for induction of the regenerative program following axon injury, it is not known whether activation of DLK is sufficient to activate this program in the absence of injury, or to enhance the regenerative capacity following injury. Improvements to regeneration in the PNS would have important clinical consequences, since the slow pace of endogenous regeneration is the key obstacle to functional recovery. Finally, what mechanisms regulate DLK signaling? Identification of proteins that modulate DLK- dependent signaling will generate novel therapeutic targets for the diseased or injured nervous system. If successful, this work will significantly advance our understanding of the function, regulation, and therapeutic potential of the DLK pathway.

Public Health Relevance

Axons are particularly vulnerable to injury and disease, and axon damage is a hallmark of many neurological disorders. The dual leucine zipper kinase (DLK) is a key sensor of axon injury that regulates the three primary neuronal responses to axon injury-axon degeneration, axon regeneration, and neuronal cell death, and so is a therapeutic candidate for a wide range of neurological diseases. Here we investigate the function, regulation, and therapeutic potential of the DLK pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065053-07
Application #
9086445
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakeman, Lyn B
Project Start
2010-01-18
Project End
2020-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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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
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
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
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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