SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration.

Yo Sasaki,Norimitsu Ban,Aaron Diantonio,Sanford L Boye,Shannon E Boye,Hiroki Kakita,Rajendra S Apte,Shunsuke Kubota,Joseph B Lin,Zhenyu Dong,Abdoulaye Sene,Tae Jun Lee,Jeffrey Milbrandt

doi:10.7554/elife.62027

Yo Sasaki, Norimitsu Ban + Show 11 more

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https://doi.org/10.7554/elife.62027

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Abstract

Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.

Highlights

Leber congenital amaurosis (LCA) is a retinal degenerative disease characterized by childhood onset and severe loss of vision
NMNAT1 is indispensable for mouse development (Conforti et al, 2011) and recent studies identified causative mutations in NMNAT1 in patients with Leber congenital amaurosis type 9 (LCA9), a disorder associated with severe, early-onset retinal degeneration and vision loss (Falk et al, 2012; Perrault et al, 2012; Koenekoop et al, 2012; Chiang et al, 2012; Coppieters et al, 2015; Khan et al, 2018)
LacZ staining was detected in the retinal pigment epithelium (RPE), photoreceptor outer segments (OS), inner segments (IS), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), and ganglion cell layer (GCL) suggesting the ubiquitous expression of NMNAT1 in retina (Figure 1—figure supplement 1A)

Summary

Introduction

Leber congenital amaurosis (LCA) is a retinal degenerative disease characterized by childhood onset and severe loss of vision. Many of the enzymes involved in photoreceptor function are dependent on NAD+ as a cofactor, and for some of these proteins mutations in their corresponding genes lead to blindness. In photoreceptors NMNAT1 is present in photoreceptor outer segments (Zhao et al, 2016), consistent with an additional, extra-nuclear role of NMNAT1 in photoreceptor cells This is of particular interest because engineered non-nuclear variants of enzymatically-active NMNAT1 can potently inhibit pathological axon degeneration, which is commonly observed in the early stages of many neurodegenerative disorders (Walker et al, 2017; Sasaki et al, 2009; Babetto et al, 2010). Since the SARM1 pathway is likely druggable (DiAntonio, 2019; Krauss et al, 2020), these findings provide a framework for developing new therapeutic strategies for treating patients with LCA9 and potentially other retinal disorders

Results

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Materials and methods

Funding Funder National Institute on Aging