Student Theses and Dissertations


Deanna Belsky

Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Tessier-Lavigne Laboratory


Amyotrophic Lateral Sclerosis is a neurodegenerative disorder characterized by progressive muscle denervation, motor axon degeneration and the death of motor neurons. The molecular mechanisms that mediate axon degeneration in ALS remain unknown, but motor neuron cell body death occurs through apoptosis. Genetic deletion of the pro-apoptotic gene Bax delays muscle denervation, prolongs disease onset, prevents motor neuron cell death and improves survival in an ALS mouse model. However, the timing and extent of axon degeneration in these mice is unaffected. Here, we examine the role of Sarm1, a component of the Wallerian degeneration pathway, and its interaction with the classical apoptotic cascade in ALS. Consistent with previous work, we find that genetic deletion of Bax delays symptom onset and extends lifespan of SOD-1G93A transgenic mice. In contrast, elimination of Sarm1 modestly delays axon degeneration at later stages of the disease without affecting lifespan. Genetic block of both pathways delays symptom onset, prolongs survival, and decreases disease burden by significantly reducing, by half, the number of days that mice exhibit disease-related symptoms. Our results demonstrate divergent and mutually reinforcing roles for the apoptotic and Wallerian degeneration pathways in ALS and suggest the presence of a molecularly distinct pathway that mediates disease progression.


A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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