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 6

Sarm1 KO rescues the decline in RGC function in Opa1R290Q/+ mice.

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Sarm1 KO rescues the decline in RGC function in Opa1R290Q/+ mice. (A an...
(A and B) Quantification of N1 amplitudes of flash VEPs and pattern VEPs measured at the indicated ages of the cohorts. Each dot represents 1 animal. Amplitudes were normalized to the WT average at each age. n = 15–18 Opa1+/+ Sarm1–/+, n = 16–17 Opa1R290Q/+ Sarm1–/+, and n = 15–17 Opa1R290Q/+ Sarm1–/– mice per age group. One-way ANOVA followed by Tukey’s multiple-comparison test. Box plots denote minimum, first quartile, median, third quartile, and maximum values. (C and D) Average flash VEP and pattern VEP traces in 18MO animals. Data indicate the mean ± SEM. (E) Normalized CAP traces from the 3 genotypes at the 2 highest light intensities. Data indicate the mean ± SD. Stimulus monitor traces are shown at the bottom. The Opa1+/+ Sarm1–/+ traces were superimposed onto the other 2 groups for comparisons. n = 4–5 Opa1+/+ Sarm1–/+, n = 8–9 Opa1R290Q/+ Sarm1–/+, and n = 7 Opa1R290Q/+ Sarm1–/– retinas. (F) Ratio of the second and first ON peaks (ON P2/P1) as a function of light intensities from E. Data indicate the mean ± SD. Mann-Whitney U test with bootstrapping (see Methods). P values for all comparisons are presented in the Supporting Data Values file. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001; #P < 0.05 between Opa1+/+ Sarm1–/+ and Opa1R290Q/+ Sarm1–/+ retinas; and †P < 0.05 between Opa1R290Q/+ Sarm1–/+ and Opa1R290Q/+ Sarm1–/– retinas.