SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration.

Laura K Finnegan,Naomi Chadderton,Arpad Palfi,G Jane Farrar,Michael Carty,Andrew G Bowie,Paul F Kenna,Sophia Millington-Ward

doi:10.3390/ijms23031606

Abstract

The challenge of developing gene therapies for genetic forms of blindness is heightened by the heterogeneity of these conditions. However, mechanistic commonalities indicate key pathways that may be targeted in a gene-independent approach. Mitochondrial dysfunction and axon degeneration are common features of many neurodegenerative conditions including retinal degenerations. Here we explore the neuroprotective effect afforded by the absence of sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a prodegenerative NADase, in a rotenone-induced mouse model of retinal ganglion cell loss and visual dysfunction. Sarm1 knockout mice retain visual function after rotenone insult, displaying preservation of photopic negative response following rotenone treatment in addition to significantly higher optokinetic response measurements than wild type mice following rotenone. Protection of spatial vision is sustained over time in both sexes and is accompanied by increased RGC survival and additionally preservation of axonal density in optic nerves of Sarm1−/− mice insulted with rotenone. Primary fibroblasts extracted from Sarm1−/− mice demonstrate an increased oxygen consumption rate relative to those from wild type mice, with significantly higher basal, maximal and spare respiratory capacity. Collectively, our data indicate that Sarm1 ablation increases mitochondrial bioenergetics and confers histological and functional protection in vivo in the mouse retina against mitochondrial dysfunction, a hallmark of many neurodegenerative conditions including a variety of ocular disorders.

Highlights

Introduction published maps and institutional affilRetinal ganglion cells (RGCs) constitute approximately 1% of retinal cells but are vital for vision, integrating visual information from the retinal layers and transmitting this information to the brain via the optic nerve
The objective of the study was to evaluate whether ablation of sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a key component of the axon degeneration pathway, could protect against complex I deficiency, mitochondrial dysfunction and subsequent vision loss in a well-established chemically induced mouse model of retinal degeneration [44,45,46]
We evaluated whether ablation of SARM1 protected against the decline in spatial vision that occurs following loss of RGCs

Summary

Introduction

Introduction published maps and institutional affilRetinal ganglion cells (RGCs) constitute approximately 1% of retinal cells but are vital for vision, integrating visual information from the retinal layers and transmitting this information to the brain via the optic nerve. When RGCs or their axons, which form the optic nerve, are damaged and degenerate, vision is compromised or lost. These cells are affected in many degenerative conditions, including glaucoma, Leber hereditary optic neuropathy (LHON) and Parkinson’s and Alzheimer’s diseases [1,2,3]. These diseases have different mechanisms of action—glaucoma can involve increased pressure on RGCs leading to axonal degeneration and cell death, while LHON is a mitochondrially inherited neuropathy that primarily affects RGCs—protection against the death of these cells could, in principle, be beneficial in many disease settings. RGC death and vision loss through ablation of sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a prodegenerative NADase. iations.

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