Axon degeneration occurs after nervous system injury and during neurodegenerative diseases but very little is known about how injured or diseased axons destroy themselves. Recent work on the mouse Wallerian degeneration slow molecule (Wlds), which potently protects severed axons from degeneration, has revealed that axon degeneration is an active process of axon auto-destruction. Amazingly, Wlds can also suppress axon degeneration after chemical insult and delay disease onset in a number of mouse models of human neurodegenerative disease. Wlds is therefore a broadly neuroprotective molecule and understanding its molecular action is of paramount importance. We have developed the first Drosophila model to study injury-induced axon degeneration and shown that mouse Wlds can also potently suppress axon degeneration in severed Drosophila axons. These data indicate that the molecular mechanism that drive axon auto-destruction after injury are well-conserved in Drosophila and mammals, and open the door to powerful molecular-genetic approaches only available in Drosophila to study axon auto-destruction. In this proposal we will: (1) define the domains of the Wlds protein essential for it to protect axons;(2) determine whether Wlds interacts with the ubiquitin proteasome, NAD biosynthetic, or apoptotic machinery to block axon auto-destruction;and (3) perform the first ever forward genetic screens for mutation that block axon degeneration after injury or Wlds neuroprotective function. These studies represent the beginning of a long-term comprehensive effort to understand how axons destroy themselves after injury, and how Wlds impinges upon these pathways. We expect our findings to have a major impact on our understanding of axon degeneration after injury or during disease in humans, and the novel molecules we identify will be excellent candidates for therapeutic intervention in human axonopathies.

Public Health Relevance

After brain injury or during neurological disease neuronal fibers degenerate, connections in the brain are lost, and neural function is irreversibly compromised. We are studying the cellular action of an extraordinary molecule, WldS, which suppresses this loss of neuronal fibers. Our work will identify many new molecules that will be targets for treatment of patients after brain injury or during neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059991-02
Application #
7563926
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Kleitman, Naomi
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2009
Total Cost
$355,469
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Francis, Michael M; Freeman, Marc R (2016) Dendrites actively restrain axon outgrowth and regeneration. Proc Natl Acad Sci U S A 113:5465-6
Sreedharan, Jemeen; Neukomm, Lukas J; Brown Jr, Robert H et al. (2015) Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2. Curr Biol 25:2130-6
Neukomm, Lukas J; Freeman, Marc R (2014) Diverse cellular and molecular modes of axon degeneration. Trends Cell Biol 24:515-23
Neukomm, Lukas J; Burdett, Thomas C; Gonzalez, Michael A et al. (2014) Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila. Proc Natl Acad Sci U S A 111:9965-70
Freeman, Marc R (2014) Signaling mechanisms regulating Wallerian degeneration. Curr Opin Neurobiol 27:224-31
Rooney, Timothy M; Freeman, Marc R (2014) Drosophila models of neuronal injury. ILAR J 54:291-5
Milde, Stefan; Fox, A Nicole; Freeman, Marc R et al. (2013) Deletions within its subcellular targeting domain enhance the axon protective capacity of Nmnat2 in vivo. Sci Rep 3:2567
Wishart, Thomas M; Rooney, Timothy M; Lamont, Douglas J et al. (2012) Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo. PLoS Genet 8:e1002936
Avery, Michelle A; Rooney, Timothy M; Pandya, Jignesh D et al. (2012) WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr Biol 22:596-600
Osterloh, Jeannette M; Yang, Jing; Rooney, Timothy M et al. (2012) dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337:481-4

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