Mechanisms of Axon Regeneration and Degeneration in Caenorhabditis elegans

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Hammarlund, Marc

Abstract

The nervous system is remarkably resilient, yet axons remain highly vulnerable to injury. In response to damage, axon regeneration serves as a conserved and fundamental process that enables neurons to restore function after injury. In contrast, axon degeneration is a progressive and active breakdown that can occur as the result of traumatic injury, disease, or cellular stress. The molecular mechanisms governing the interplay between axon regeneration and degeneration are not fully understood. In this study, I investigate key molecular pathways that regulate axon integrity, degeneration, and repair. I first demonstrate the essential, cell-intrinsic role of the spectrin-based membrane periodic cytoskeleton in maintaining the structural integrity of GABAergic motor neurons. Next, I characterize the dual role of the amyloid precursor-like protein (APL-1) in inhibiting axon regeneration and promoting degeneration, furthering our understanding of the function of the amyloid precursor protein family in the mature nervous system. Finally, I examine how cellular stress and metal homeostasis influence neuronal resilience by characterizing the importance of the unfolded protein response and iron metabolism for axon regeneration. Together, these findings reveal four distinct mechanisms that govern axon regeneration and degeneration, offering insights into the molecular pathways that shape neuronal health.

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