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 7

SARM1 is present in the mitochondrial IMS and IMM, and its KO does not rescue mitochondrial fragmentation.

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SARM1 is present in the mitochondrial IMS and IMM, and its KO does not r...
(A) Confocal images of overexpressed SARM1 and the mitochondrial matrix marker MitoDsRed in cortical neurons show mitochondrial localization of SARM1 in both WT and Opa1R290Q/+ neurons. MAP2 staining is shown in blue. Scale bars: 10 μm. (B) Western blot of SARM1, TOMM20, TIM23, cytochrome C (Cyt C), and HSP60 in the cytosolic and crude mitochondrial fractions from WT whole brain tissues. (C) Diagram depicting localization of the marker proteins across different mitochondrial compartments. (D) PK protection assay on crude mitochondrial fractions from WT whole brain samples. (E) Quantification of SARM1 abundance across 6 conditions. n = 4 mice from 4 experiments. Protein levels were normalized to the control condition in each experiment. Data indicate the mean ± SEM. (F) Representative confocal images of mitochondria in expanded cortical neurons (DIV8–DIV9) isolated from Opa1+/+ Sarm1–/+, Opa1R290Q/+ Sarm1–/+, and Opa1R290Q/+ Sarm1–/– mice. Mitochondria are labeled with MitoDsRed. Scale bars: 10 μm. (G) Quantification of mitochondria length in OPA1 Sarm1 cortical neurons shows no rescue of fragmentation by Sarm1 KO (n = 33 Opa1+/+ Sarm1–/+, 24 Opa1R290Q/+ Sarm1–/+, and 38 Opa1R290Q/+ Sarm1–/– neurons from 4 experiments). Box plots denote minimum, first quartile, median, third quartile, and maximum values. **P < 0.01 and ****P < 0.0001, by 1-way ANOVA with Tukey’s multiple-comparison test (E and G). Tx, Triton X-100.