"Seats of Destruction": Axonal Spheroids as Targets for Glial Responses to Peripheral Nerve Injury

Axon degeneration underlies debilitating axonal pathologies such as traumatic brain injury, peripheral neuropathies, and motor neuropathies. Furthermore, axon degeneration drives neuronal death, giving rise to cell body death in many pathological and all developmental neurodegenerative contexts. Axonal spheroids are hallmark features of neurodegeneration, forming along degenerating axons and contributing to disease progression. However, the dynamics of spheroid disappearance, as well as their interactions with glial cells, remain poorly understood. Given that spheroids are present across all degenerative etiologies and that they are increasingly implicated in functional deficits of the nervous system, it is imperative to understand whether and how the surrounding environment regulates spheroids for both basic and translational applications. This dissertation explores how neighboring glial cells interact with axonal spheroids during degeneration, identifying spheroids as key targets of glial responses to peripheral nerve injury. We first distill the guiding research questions in Chapter 1, which reviews axon degeneration pathways and spheroid biology from the pre-existing literature. Chapter 2 (as published in Glial Health Research) develops a peripheral nerve injury model for studying spheroid dynamics and their regulation by Schwann cells (SCs) in vivo, revealing for the first time that the extracellular environment targets spheroids as part of the nerve injury response. Chapter 3 builds on this by examining phagocytosis as a pathway for these spheroid-targeted responses. Specifically, it characterizes how spheroid engulfment influences degeneration outcomes, and identifies an additional glial cell type, macrophages, that compensate when SCs are perturbed. Chapter 4 synthesizes all of these findings, discusses their broader implications, and outlines future research directions. These insights not only advance our basic understanding of neurodegeneration, but also identify spheroids as promising therapeutic targets that could transform our future approaches to treating devastating disorders.