Exploring SARM1 as a target to delay programmed axon degeneration

Programmed axon degeneration (Wallerian degeneration) can occur after physical injury, inhibition of axon transport, exposure to neurotoxic compounds, and in diseases involving mitochondrial or metabolic dysfunction. There is increasing evidence that this pathway can be activated in human painful neuropathies and preclinical evidence suggests it is also active in neurodegenerative conditions, such as Parkinson’s disease and Amyotrophic Lateral Sclerosis. Programmed axon degeneration is a potentially druggable pathway with preclinical studies showing that increasing levels of pro-survival factor NMNAT2, and removal of MYCBP2 involved in protein ubiquitination and turnover, or prodegenerative protein SARM1 can delay programmed axon degeneration. Preclinical studies indicate that complete genetic removal of Sarm1 leads to the strongest protection in vivo after physical transection injury and also prevents perinatal lethality in mice lacking NMNAT2. This makes SARM1 an attractive protein to explore in the context of delaying programmed axon degeneration for therapeutic effect. However, until this thesis, the extent to which SARM1 activity needs to be decreased has been unclear. This thesis explores the possibility of targeting the SARM1 protein for therapeutic effect. Firstly, since decreasing protein levels or activity is more achievable than completely eliminating them, the effect of Sarm1 hemizygosity in mice was assessed. Data presented here show that the rate of programmed axon degeneration can be slowed by the absence of one allele after in vivo transection injury, and axon outgrowth deficits in a developmental system where the pathway is active can be partially restored. Degeneration can also be slowed after a range of in vitro triggers of programmed axon degeneration showing clearly that decreasing (and not just removing) SARM1 can be beneficial. Secondly, targeting SARM1 through antisense oligonucleotides shows that SARM1 protein levels can be decreased in vitro to a similar extent as Sarm1 hemizygosity using exogenously-applied nucleotides. This decrease in protein levels confers a delay in programmed axon degeneration in a range of in vitro models suggesting that targeting SARM1 is a viable therapeutic approach. Finally, use of a non-transgenic dietary model of sporadic Alzheimer’s disease (sAD) was used to explore links between sAD and programmed axon degeneration but no differences in axon transport or signs of programmed axon degeneration were detected in this model. Nevertheless, this thesis demonstrates that targeting SARM1 pharmacologically is feasible and can delay degeneration after diverse triggers. Thus, further research into the relevant in vivo disease models could advance this strategy towards clinical application.