Abstract
SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.
Competing Interest Statement
MPC consults for Nura Bio and Drishti Discoveries and the Coleman group is part funded by AstraZeneca for academic research projects but none of these activities relate to the study reported here. DLB has consulted for AstraZeneca and Lilly on behalf of Oxford University Innovation and received research grants from AstraZeneca and Lilly but none of these activities relate to these studies. HTZ is a full-time employee and stock holder of Ionis Pharmaceuticals, Inc. AL and PA-F are inventors on a patent application related to the subject matter of the publication.
