ORCID
https://orcid.org/0000-0003-3844-4275
Date of Award
Summer 8-15-2016
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Axons are neuronal projections that can extend for up to a meter to wire the nervous system over large distances. The incredible length of an axon makes it vulnerable to both injury and disease. Axonal integrity is actively regulated by the neuron and is controlled by a tight balance of pro-degenerative and pro-survival factors. NMNAT2, a NAD+-synthesizing enzyme, is a labile axon survival factor that is synthesized in the cell body and transported into the distal axon. NMNAT2 functions as a rheostat within the axon, such that when levels fall below a critical threshold, axon degeneration factors are activated. Axon degeneration is promoted by signaling from a mitogen-activated protein kinase (MAPK) cascade as well as the central regulator of axon degeneration, SARM1. While manipulating pro-degenerative and pro-survival factors can influence the progression of axon degeneration, a molecular pathway to unite these factors was unknown. Here, I demonstrate that MAPKs function upstream of SARM1 by dampening levels of axonal survival factors NMNAT2 and SCG10, a microtubule-binding protein. After axon injury, blocked axonal transport coupled with ongoing MAPK-dependent degradation causes depletion of NMNAT2 and subsequent activation of SARM1 and axon destruction. Importantly, these findings place major components of the axonal degeneration program into a linear molecular pathway and reveal drug targets that may be therapeutically beneficial.
Language
English (en)
Chair and Committee
Aaron DiAntonio
Committee Members
Jeffrey Milbrandt, Kelly Monk, Shin-ichiro Imai, Paul Taghert
Recommended Citation
Walker, Lauren, "Defining the Role of MAPK Signaling in the Axonal Degeneration Pathway" (2016). Arts & Sciences Electronic Theses and Dissertations. 903.
https://openscholarship.wustl.edu/art_sci_etds/903
Comments
Permanent URL: https://doi.org/doi:10.7936/K7542M0C