ORCID

https://orcid.org/0000-0001-7459-2932

Date of Award

Spring 5-15-2016

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 extensions that make up the wiring of the nervous system. Recent studies have revealed that axons possess a unique and largely uncharacterized self-destruction program that may be a therapeutic target for diseases in which axon loss contributes to disability. We have developed a scalable assay of axon degeneration that allows quantitative screening for agents that alter axon degeneration. From a library of bioactive compounds, we have identified and characterized several novel axon-protective compounds. Using this system we screened a genome-scale lentiviral shRNA library to identify proteins that promote axon degeneration following injury. A top hit in this screen was the protein SARM1, and validation experiments and the work of others confirm that SARM1 is a central regulator of axon destruction. Combining structure-function and biochemical studies, we have developed a working model of SARM1-mediated axon destruction: SARM1 complexes are present within axons and are held inactive by an auto-inhibitory N-terminus. Following injury, SARM1 activation leads to dimerization of the SARM1 Toll-Interleukin Receptor (TIR) domain, which is sufficient to trigger a program of rapid NAD+ breakdown leading to axon destruction.

Language

English (en)

Chair and Committee

Jeffrey Milbrandt

Committee Members

Aaron DiAntonio, Valeria Cavalli, Marc Diamond, Shin-Ichiro Imai,

Comments

Permanent URL: https://doi.org/10.7936/K7RB72WN

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