Programmed axon death as a driver of environmental neurotoxicity triggered by pyridine derivatives

Programmed axon death is a well-characterized, preventable pathway leading to axon degeneration. Programmed axon death is regulated by SARM1, a pro-degenerative, multi- functional enzyme that consumes NAD and NADP, with dramatic consequences for neuron energy metabolism. Accumulating evidence in both pre-clinical disease models and in human disease suggests that programmed axon death contributes to neurodegeneration in humans, including in toxic neuropathies, ALS, and polyneuropathies. An important link has been established between programmed axon death and environmental compounds associated with neuropathy, such as mitochondrial toxins, environmental pesticides, rodenticides, and chemotherapy drugs. Among these, pyridines have arisen as an important focus for programmed axon death. Pyridines are versatile molecules that are frequently incorporated in drugs and pesticides. Our previous research has demonstrated that the pyridine derivative vacor, a disused rodenticide and lethal neurotoxin, is a specific SARM1 activator thereby inducing axon death and neurodegeneration. In this thesis, we identify and characterise additional pyridine derivatives causing SARM1-dependent axon degeneration, including 3- acetylpyridine, 6-aminonicotinamide, 2-aminopyridine and pyridoxine (vitamin B6). We show that programmed axon death is a ubiquitous neurodegenerative mechanism triggered by environmental pyridines, and preventable via genetic deletion or knock-down of Sarm1 in mouse, human and zebrafish models. Currently, the mechanism underlying programmed axon death initiation by many environmental molecules is unclear. We report that structurally similar molecules trigger programmed axon death in distinct ways, including direct SARM1 activation, inhibition of upstream pathway regulators such as NMNAT2, or via cell body death mechanisms, while also triggering distinct SARM1 enzymatic activities. These findings suggest that SARM1 mediates environmental neurotoxicity and contributes to toxic neuropathies induced by various molecules through different activation mechanisms, raising the question of whether other environmental chemicals or structurally similar drugs in use today also activate programmed axon death. Finally, we show that genetic mutations affecting programmed axon death regulators such as NMNAT2 and SARM1 increase susceptibility to environmental pyridines in vitro, including in rare human SARM1 mutations first identified in patients with motor nerve disorders. As mutations in NMNAT2 and SARM1 have been previously linked to disease, individuals carrying them may be at higher risk of developing neuropathology linked to environmental factors.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Merlini, Elisa

Advisor dc:contributor.advisor

• Coleman, Michael

• Axon degeneration
• toxic neuropathy
• SARM1
• Wallerian degeneration
• Programmed axon death

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/41673b9b-df55-492d-91d5-81ef7b796f52/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.114157

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/377294