SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Abstract

Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD + synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD + homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration.To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of photoreceptors, indicating these cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the photoreceptor, as conditional deletion of NMNAT1 in photoreceptors but not retinal pigment epithelial cells is sufficient to cause photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving photoreceptor cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway that is active in the setting of dysregulated NAD + metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.

Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons

“…Interestingly, using a recently validated metabolic marker of SARM1 activity (cADPR) (Sasaki et al, 2020b), we do not detect SARM1 involvement at pre- or post-degenerative timepoints in our model. That we do not find evidence of SARM1 involvement, even in the presence of increased levels of its potent activator NMN (Zhao et al, 2019; Figley et al, 2021) is unexpected but not implausible, especially considering the fact that the report implicating SARM1 in NMNAT1-associated degeneration deleted NMNAT1 in mature mice (Sasaki et al, 2020a).…”

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity

“…The IVT vacor model we have developed could also be used for relatively rapid validation of drugs targeting SARM1 in vivo in rodents, with both morphological and functional readouts. Our data also show that SARM1 activation is sufficient to drive degeneration of multiple types of retinal neuron in addition to photoreceptors (Sasaki et al, 2020b), making SARM1 a promising target to treat retinal degeneration.…”

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

“…As well as its established role in axons, SARM1 can promote neuronal cell death under certain conditions (Gerdts et al, 2013; Summers et al, 2014; Gerdts et al, 2015; Summers et al, 2016; Bratkowski et al, 2020), although to what extent the cell death and concurrent axon degeneration are primary or secondary events has not been determined. However, recent studies do suggest direct involvement of SARM1 in neuronal cell death in some situations, including photoreceptor loss in models of retinal degeneration and Leber congenital amaurosis (LCA) (Ozaki et al, 2020; Sasaki et al, 2020) and as a result of Vacor neurotoxicity when specifically applied to cell bodies (Loreto et al, 2020).…”