title: Local axonal protection by WldS as revealed by conditional regulation of protein stability.
abstract: 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 postinjury 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.
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305; jtw@alumni.stanford.edu barres@stanford.edu.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Medress
authors.affiliation: Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, CA 90095.
authors.forename: Mauricio E
authors.initials: ME
authors.lastname: Vargas
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305; jtw@alumni.stanford.edu barres@stanford.edu.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008959:Models, Neurological; D009249:NADP / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009422:Nervous System Diseases / Q000473:pathology; D055550:Protein Stability; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D013997:Time Factors; D014162:Transfection; D014855:Wallerian Degeneration / Q000378:metabolism* / Q000473:pathology
chemical_list: D008024:Ligands; D009419:Nerve Tissue Proteins; C533642:Wld protein, rat; D009249:NADP
keywords: NAD+; Wallerian degeneration; WldS; axon degeneration; axotomy