The molecular intersection between axon-specific pruning and neuronal apoptosis

Cusack, Corey Leigh

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March 20, 2019

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Cusack, Corey Leigh
- Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum

Abstract

Neurons can activate pathways to either destroy the whole cell via apoptosis or specifically degenerate only the axon. Axon-specific degeneration, also known as pruning, is required to establish and refine neuronal connections during development and to permit plasticity in the adult nervous system. Aberrant axon degeneration is also observed in several neurodegenerative diseases and can long precede cell body death in neurons. However, despite its biological importance and clinical relevance, the exact mechanism underlying axon degeneration remains unclear. Apoptosis and axon degeneration pathways were widely recognized to be distinct based on the prevalent axotomy-induced model of axon removal called Wallerian degeneration. Five years ago, however, it was discovered that developmental axon pruning induced by axon-specific trophic factor deprivation required the key apoptotic protein Bax as well as a caspase, caspase-6. Several studies, including work described here, also demonstrate the requirement of the classically apoptotic caspases-9 and -3 in axon pruning. This dissertation examines several critical questions raised by these unanticipated findings: Are other components of apoptosis also involved in axon degeneration? How can neurons activate Bax to selectively degenerate axons without simultaneously triggering apoptosis? What is the exact mechanism for activating caspase-6 during axon degeneration? By applying the lab's expertise in neuronal apoptosis and adapting microfluidic technology to study axon-specific degeneration, I have uncovered several novel aspects about the molecular points of overlap and distinction between neuronal apoptosis (where both axons and somata degenerate) and axon pruning (where only axons degenerate). This work is the first to distinguish that caspase-6 is essential for axon degeneration that occurs during pruning but not apoptosis. Second, while apoptosis requires both Apaf-1 and caspase-9, axon pruning requires caspase-9 but not Apaf-1. Third, I found that neurons utilize both the potent endogenous caspase inhibitor XIAP and the proteasome to compartmentalize axonal caspase activation and protect the soma. Fourth, this work demonstrates that mature neurons are exquisitely capable of selectively restricting apoptosis while permitting axon-specific degeneration. Lastly, I have also focused on how transcription, translation, and the localization of BH3-only proteins and the microRNA, miR-29, may facilitate axon-specific Bax activation.

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