Abstract

Researchers have realized a common mechanism in traumatic injury and multiple neurodegenerative diseases: when neuronal metabolism is disrupted, axons undergo an intrinsic programmed degeneration process. In this process, the key executor is SARM1, a TIR domain NADase enzyme that senses the NMN/NAD+ ratio in neurons. When NAD+ level declines or NMN accumulates, SARM1 is activated and leads to axon degeneration. In recent years, this signaling pathway has been recognized as a key mediator of axon degeneration in various neurodegenerative diseases. During my Ph.D., I investigated how SARM1 activation is triggered by environmental toxins and DNA damage-induced cell death, broadening our understanding of SARM1’s role beyond classical axonal injury. In my first study, I found some neurotoxins can be converted into potent SARM1 activators in cells. Specifically, we found the Nam analog 3-AP, can be converted into 3-APMN in neurons, which binds to the allosteric NMN-binding site and activates SARM1. This process leads to NAD+ depletion, cADPR generation, axon degeneration and neuronal death. We have validated the molecular mechanism and confirmed corresponding phenotypes in both in vitro neuronal cultures and in mouse models. These results demonstrate that exogenous neurotoxins can mimic the role of NMN to activate SARM1, therefore causing pathological axon degeneration. In my second study, I further demonstrated that SARM1 is a crucial component of neuronal Parthanatos and excitotoxic neuronal death. Parthanatos is a type of programmed cell death characterized by excessive PARP1 activation after DNA damage. My research revealed that, once PARP1 is activates, SARM1 is subsequently activated, leading to mitochondrial depolarization, AIF translocation and neuronal death. Importantly, inhibiting SARM1 can effectively prevent the progression of neuronal death and rescue neuropathological phenotypes. Overall, my studies elucidate the nexus role of SARM1 in pathological axon degeneration and neuronal death. SARM1 activation can be triggered by disruption of the NMN/NAD+ ratio, which can come from the accumulation of NMN analogs, or substantial NAD+ declines caused by other NADase enzymes like PARP1. In addition, SARM1 plays an essential role in executing neuronal Parthanatos and excitotoxic cell death. Besides revealing novel biological mechanisms, my research provides some important therapeutic insights. Firstly, 3-AP or other pyridine-based neurotoxins can be used as potential neurolytic agents to selectively degenerate axonal terminals. Moreover, targeting SARM1 provides promising strategies for treatment in DNA damage-associated ALS, Parkinson’s disease, and stroke. Together, my work broadens the biological understanding of SARM1-mediated neurodegeneration and highlights its therapeutic potential for pain treatment and neurodegenerative diseases.

Committee Chair

Jeffrey Milbrandt

Committee Members

Aaron DiAntonio; Jianmin Cui; Robi Mitra; Sheng Chih Jin

Degree

Doctor of Philosophy (PhD)

Author's Department

Biomedical Engineering

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

12-19-2025

Language

English (en)

Download

Available for download on Saturday, December 18, 2027

Share

COinS