Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 33, Pages 10093-10100Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1508337112
Keywords
axon degeneration; Wallerian degeneration; WldS; axotomy; NAD(+)
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Funding
- National Eye Institute [R01 EY11030]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Johnson and Johnson Innovation Fund
- Howard Hughes Medical Institute Graduate Research Fellowship
- American Heart Association Pre-Doctoral Fellowship
- Stanford Bio-X Graduate Fellowship
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The expression of the mutant Wallerian degeneration slow (WldS) protein significantly delays axonal degeneration from various nerve injuries and in multiple species; however, the mechanism for its axonal protective property remains unclear. Although WldS is localized predominantly in the nucleus, it also is present in a smaller axonal pool, leading to conflicting models to account for the WldS fraction necessary for axonal protection. To identify where WldS activity is required to delay axonal degeneration, we adopted a method to alter the temporal expression of WldS protein in neurons by chemically regulating its protein stability. We demonstrate that continuous WldS activity in the axonal compartment is both necessary and sufficient to delay axonal degeneration. Furthermore, by specifically increasing axonal WldS expression postaxotomy, we reveal a critical period of 4-5 h post-injury during which the course of Wallerian axonal degeneration can be halted. Finally, we show that NAD+, the metabolite of WldS/nicotinamide mononucleotide adenylyltransferase enzymatic activity, is sufficient and specific to confer WldS-like axon protection and is a likely molecular mediator of WldS axon protection. The results delineate a therapeutic window in which the course of Wallerian degeneration can be delayed even after injures have occurred and help narrow the molecular targets of WldS activity to events within the axonal compartment.
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