SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy
Chen Ding, … , Michael Tri H. Do, Thomas L. Schwarz
Chen Ding, … , Michael Tri H. Do, Thomas L. Schwarz
Published May 9, 2025
Citation Information: J Clin Invest. 2025;135(12):e191315. https://doi.org/10.1172/JCI191315.
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Research Article Cell biology Neuroscience

SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy

Abstract

Autosomal dominant optic atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the optic atrophy type 1 (OPA1) gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified sterile alpha and TIR motif containing 1 (SARM1), a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we show that a portion of SARM1 localized within the mitochondrial intermembrane space. These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.

Authors

Chen Ding, Papa S. Ndiaye, Sydney R. Campbell, Michelle Y. Fry, Jincheng Gong, Sophia R. Wienbar, Whitney Gibbs, Philippe Morquette, Luke H. Chao, Michael Tri H. Do, Thomas L. Schwarz

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Figure 2

Age-related RGC and optic nerve degeneration in Opa1R290Q/+ mice.

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Age-related RGC and optic nerve degeneration in Opa1R290Q/+ mice. (A) Re...
(A) Representative images of retinal whole mounts from WT and Opa1R290Q/+ mice. Each retina was imaged in every quadrant, approximately 1.2 mm from the optic nerve head. RBPMS (green) marks all RGCs and p-H2Ax (magenta) labels RGCs undergoing cell death (marked by arrowheads). Scale bars: 20 μm. (B) Quantification of dying RGCs over time. Each dot represents 1 retina. The counts of dying RGCs were averaged across the 4 quadrants of each retina and divided by the average RGC number of those quadrants. This value was then normalized to the WT average at each age. n = 9–12 WT and n = 9–14 Opa1R290Q/+ retinas per age group. (C) Quantification of total RGCs over time. Each dot represents 1 retina. RGC counts were first averaged across the 4 quadrants of each retina and then normalized to the WT average at each age. n = 6–10 WT and n = 8–10 Opa1R290Q/+ retinas per age group. (D) Diagram of optic nerve cross-sections and representative EM images from 12MO animals. Arrows indicate degenerating axons. Scale bars: 1 μm. Diagram was created with BioRender. (E) Quantification of degenerating axons. Each dot represents 1 optic nerve. The counts of degenerating axons were averaged across the 9 fields of each cross-section of an optic nerve and divided by the average axon number of those fields. This value was then normalized to the WT average at each age. n = 6–8 WT and n = 8 Opa1R290Q/+ retinas per age group. Box plots denote minimum, first quartile, median, third quartile, and maximum values. *P < 0.05, **P < 0.01, and ***P < 0.001, by Mann-Whitney U test for each age group.