Axon loss is a characteristic feature shared among various neurodegenerative disorders, regardless of their distinct primary causes. Programmed axon death is a conserved, well-characterised pathway of axon degeneration activated by physical injury and in disease states. The two main regulators of the pathway are the pro-survival NAD-synthesising enzyme NMNAT2, and the pro-degenerative NAD(P)-consuming enzyme SARM1. Over-expression of NMNAT enzymatic activity and removal of SARM1 can significantly delay axon degeneration following numerous neurodegenerative stressors in vitro and in several disease models in vivo, including traumatic brain injury, Parkinson’s disease and glaucoma. Association of these components with human disease is becoming increasingly apparent, with mutations in NMNAT2 identified in patients with polyneuropathy and hyperactive SARM1 variants found to be enriched in patients with motor nerve disorders. While the pathway’s role in axon degeneration caused by acute insults has been well characterised, the emerging clinical data highlight the need to study the contribution of programmed axon death to chronic conditions which characterise the majority of neurodegenerative diseases.

This thesis has a multifaceted aim, seeking to investigate the possibility of partial, chronic SARM1 activation in morphologically intact axons, establish functional interactions between pathway components, and explore the mechanisms downstream of SARM1 that drive axon degeneration.

Using mice with graded levels of NMNAT2 protein, this thesis demonstrates that sub-heterozygous NMNAT2 expression reduces viability in a SARM1-dependent manner and partially activates SARM1 in primary neuronal cultures. Furthermore, the NAD precursor nicotinamide riboside (NR), can decrease NAD levels in neurites expressing low levels of NMNAT2. In an attempt to test for synergy between NMNAT2 and another axon-protective protein, Stathmin-2, it becomes evident that the proteins mediate their effects on axon maintenance through distinct pathways. Regarding mechanisms downstream of SARM1 activation, the data in this thesis support that primary neurons are able to survive with critically low NAD levels, while variations in NADP levels might represent a more appropriate indication of axon survival. Finally, NaADP, a calcium mobiliser produced by SARM1, emerges as a candidate mechanism driving axon degeneration.

The findings presented in this thesis support that sub-clinical activation of programmed axon death can occur in conditions not directly associated with axon degeneration and propose mechanisms by which SARM1 could drive the axon degeneration process.