Publication Date

2012-12-11

Availability

Embargoed

Embargo Period

2014-12-11

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2012-08-24

First Committee Member

R. Grace Zhai

Second Committee Member

Nirupa Chaudhari

Third Committee Member

John L. Bixby

Fourth Committee Member

Antonio Barrientos

Fifth Committee Member

Cornelius Boerkoel

Sixth Committee Member

Michael Kim

Seventh Committee Member

Pantelis Tsoulfas

Abstract

Neurodegeneration is a hallmark of several inherited and acquired diseases of the nervous system. Though great attention in the past has been given to understanding and mitigating neuron loss in these diseases, efforts at targeting neuron cell body death pathways have yielded modest success in preventing or delaying disease onset. Often preceding neuronal death, axon degeneration is a common pathological feature of many neurodegenerative processes, and may therefore provide a therapeutic target upstream of neuronal loss. Though formerly believed to be a passive process, recent observations concerning the destruction of distal axons following transection, referred to as “Wallerian degeneration” (WD), suggest degeneration is an actively regulated process of axon self-destruction. Though the precise mechanism(s) governing axonal destruction remain elusive, insight has been gained by the discovery of a naturally occurring mutant mouse strain in which WD is delayed, the Wallerian degeneration slow (wldS) mouse. The neuroprotective properties of wldS have been mapped to a chimeric gene Ube4b/NMNAT producing a fusion, WLDS protein. Though the precise protective function of WLDS remains controversial, it is clear that NMNAT is an important neuronal maintenance factor capable of conferring axonal protection by itself. In this dissertation, I address mechanisms underlying the axon protective properties of NMNAT and WLDS in the context of WD utilizing a multidisciplinary approach that combines mammalian primary neuronal culture systems and Drosophila genetic models.

Keywords

Wallerian degeneration; axon; NMNAT; WLDs; mitochondria; milton

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