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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065053-03
Application #
8196941
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Owens, David F
Project Start
2010-01-18
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$325,850
Indirect Cost
$111,475
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Sasaki, Yo; Nakagawa, Takashi; Mao, Xianrong et al. (2016) NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD(+) depletion. Elife 5:
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
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
Valakh, Vera; Frey, Erin; Babetto, Elisabetta et al. (2015) Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury. Neurobiol Dis 77:13-25
Frey, E; Valakh, V; Karney-Grobe, S et al. (2015) An in vitro assay to study induction of the regenerative state in sensory neurons. Exp Neurol 263:350-63
Sasaki, Yo; Margolin, Zachary; Borgo, Benjamin et al. (2015) Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants. J Biol Chem 290:17228-38
Gerdts, Josiah; Brace, E J; Sasaki, Yo et al. (2015) SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science 348:453-7
Summers, Daniel W; DiAntonio, Aaron; Milbrandt, Jeffrey (2014) Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. J Neurosci 34:9338-50
Brace, E J; Wu, Chunlai; Valakh, Vera et al. (2014) SkpA restrains synaptic terminal growth during development and promotes axonal degeneration following injury. J Neurosci 34:8398-410

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