Programmed axon death: a promising target for treating retinal and optic nerve disorders

Abstract

Programmed axon death is a druggable pathway of axon degeneration that has garnered considerable interest from pharmaceutical companies as a promising therapeutic target for various neurodegenerative disorders. In this review, we highlight mechanisms through which this pathway is activated in the retina and optic nerve, and discuss its potential significance for developing therapies for eye disorders and beyond. At the core of programmed axon death are two enzymes, NMNAT2 and SARM1, with pivotal roles in NAD metabolism. Extensive preclinical data in disease models consistently demonstrate remarkable, and in some instances, complete and enduring neuroprotection when this mechanism is targeted. Findings from animal studies are now being substantiated by genetic human data, propelling the field rapidly toward clinical translation. As we approach the clinical phase, the selection of suitable disorders for initial clinical trials targeting programmed axon death becomes crucial for their success. We delve into the multifaceted roles of programmed axon death and NAD metabolism in retinal and optic nerve disorders. We discuss the role of SARM1 beyond axon degeneration, including its potential involvement in neuronal soma death and photoreceptor degeneration. We also discuss genetic human data and environmental triggers of programmed axon death. Lastly, we touch upon potential therapeutic approaches targeting NMNATs and SARM1, as well as the nicotinamide trials for glaucoma. The extensive literature linking programmed axon death to eye disorders, along with the eye's suitability for drug delivery and visual assessments, makes retinal and optic nerve disorders strong contenders for early clinical trials targeting programmed axon death.

Fig. 1. Programmed axon death pathway and triggers.

Programmed axon death is triggered by various insults, including axotomy, neurodegenerative diseases, and exposure to environmental neurotoxins. These insults result in the depletion of NMNAT2 in the axon, a labile cytoplasmic enzyme that synthesises NAD from its precursor, NMN. NMNAT2 loss leads to an accumulation of NMN, which then binds to the pro-degenerative enzyme SARM1 and activates it. Once activated, SARM1 rapidly consumes NAD and causes axon degeneration. Notably, NMN analogues originating from environmental toxins, such as VMN and 3-APMN, can also bind and activate SARM1, bypassing the initial requirement for low NMNAT2 levels in the axon, triggering both soma and axon degeneration. This suggests that SARM1 toxicity is not restricted to axon-specific degeneration; instead, it can lead to the death of any cell that expresses sufficient levels of SARM1 and may lack compensation mechanisms. (NAM nicotinamide, 3-AP 3-acetylpyridine, NMN nicotinamide mononucleotide, VMN vacor mononucleotide, 3-APMN 3-acetylpyridine mononucleotide, NAD nicotinamide adenine dinucleotide, NADP nicotinamide adenine dinucleotide phosphate, ADPR adenosine diphosphate ribose, cADPR cyclic ADP-ribose, NAMPT nicotinamide phosphoribosyltransferase, NMNAT2 nicotinamide mononucleotide adenylyltransferase 2, SARM1 sterile alpha and TIR motif-containing protein 1).

Fig. 2. Programmed axon death, NAD metabolism and eye disorders.

This figure highlights the potential involvement of programmed axon death in the pathogenesis of various retinal disorders, emphasising the roles of NMNATs and NAD homeostasis in maintaining retinal health. Programmed axon death can be activated in retinal cells through different mechanisms. Traumatic injuries and glaucoma may decrease NMNAT2 supply to the long axons of RGCs in the optic nerve, eventually leading to NMN accumulation and SARM1 activation, causing axon degeneration. In photoreceptor neurons lacking long axons, LoF mutations in NMNAT1, causing LCA9 in humans, have been associated with SARM1-dependent photoreceptor death. This suggests that, in the eye, SARM1 toxicity extends beyond the axonal compartment to affect neuronal soma as well. Toxins, such as vacor, 3-AP and vincristine, also cause ocular toxicity, which in this case is mediated by direct binding of their mononucleotide metabolites to SARM1, resulting in its activation. Programmed axon death is a preventable and druggable pathway, and various therapeutic options are under development to target eye disorders and other neurodegenerative diseases, as listed in this figure.