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McGettigan Masters Thesis Final Draft1.81 MB
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Thesis
Hypersensitivity to SARM1-dependent degeneration in a model of chemotherapy-induced neurotoxicity
University of Iowa
Master of Science (MS), University of Iowa
Spring 2026
DOI: 10.25820/etd.008392
Abstract
Axons are essential for mediating communication between the central nervous system (CNS), the peripheral nervous system (PNS), and peripheral target tissues. Due to their extraordinary length and metabolic demands, neurons are particularly vulnerable to degeneration, including damage induced by chemotherapeutic agents. Chemotherapy-induced neurotoxicity manifests as debilitating clinical symptoms such as cognitive impairment, peripheral neuropathy, axonal degeneration, and neuronal cell death. The objective of this research was to identify and characterize the molecular pathways that regulate chemotherapy-induced axon degeneration and neuronal death in sensory neurons. Primary dorsal root ganglion neurons were cultured and manipulated genetically and pharmacologically, including lentiviral-mediated expression and CRISPR-based gene editing. Axonal degeneration and neuronal viability were quantified using live-cell fluorescence imaging and computational image analysis. Treatment with cytarabine (AraC) induced neuronal cell death consistent with DNA damage–mediated mechanisms, and loss of p53 significantly attenuated cell death following chemotherapy exposure. Additionally, applying a secondary cellular stressor potentiated axon degeneration and calcium influx, a defining feature of Wallerian degeneration. Importantly, pharmacological inhibition of SARM1 in combinatorially treated neurons prevented the enhanced calcium influx and restored degeneration levels to baseline. Collectively, these findings implicate metabolic and apoptotic signaling pathways as critical regulators of chemotherapy-induced neurotoxicity and identify potential therapeutic targets for mitigating neurodegenerative damage.
Details
- Title: Subtitle
- Hypersensitivity to SARM1-dependent degeneration in a model of chemotherapy-induced neurotoxicity
- Creators
- Lily McGettigan
- Contributors
- Dan Summers (Advisor)Christopher Stipp (Committee Member)Michael Dailey (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Integrated Biology
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008392
- Publisher
- University of Iowa
- Number of pages
- vii, 48 pages
- Copyright
- Copyright 2026 Lily McGettigan
- Language
- English
- Date submitted
- 04/23/2026
- Description illustrations
- illustrations, graphs
- Description bibliographic
- Includes bibliographical references (pages 28-34).
- Public Abstract (ETD)
Neurons, or nerve cells, are the basic building blocks of the brain and nervous system. These cells use electrical and chemical signals to help us think, move, and feel. Sensory neurons are a type of nerve cell that send information from the skin, eyes, and ears to the brain and spinal cord. Each neuron has a cell body that keeps the cell alive and a long extension called an axon that acts like a wire to transmit information.
Chemotherapy drugs save many lives, but they can also damage the nervous system. This damage, called chemotherapy-induced neurotoxicity, can cause numbness, tingling, pain, and cognitive problems. Around 30–40% of cancer patients experience these side effects, and there are currently few treatments to prevent them.
In this study, I examined how the chemotherapy drug cytarabine affects sensory neurons. Cytarabine is commonly used to treat blood cancers such as leukemia and lymphoma. I found that cytarabine damages both the nerve cell body and the axon by triggering a type of programmed cell death. A protein called p53, which normally protects DNA from damage, appears to play an important role in this process. We also explored other pathways that may contribute to axon degeneration to identify potential targets for future therapies.
Understanding how chemotherapy drugs harm nerve cells could help researchers develop treatments that protect the nervous system during cancer therapy and improve the quality of life for cancer survivors.
- Academic Unit
- Biology
- Record Identifier
- 9985176871402771
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