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ORCID

https://orcid.org/0000-0003-3844-4275

Date of Award

Summer 8-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

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

Comments

Permanent URL: https://doi.org/doi:10.7936/K7542M0C

Available for download on Saturday, August 15, 2116

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