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.
View: Text | PDF
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

×

Figure 4

Abnormal CAPs in the optic nerve of Opa1R290Q/+ mice.

Options: View larger image (or click on image) Download as PowerPoint
Abnormal CAPs in the optic nerve of Opa1R290Q/+ mice. (A) Top: The recor...
(A) Top: The recording configuration contains the retina (left) and optic nerve (center), with the latter drawn into an electrode. Bottom: Schematic showing the retina, nerve and electrode. (B) Example CAPs from a WT retina. For lower intensities (<10 R*/rod/s), at least 3 trials were typically averaged to increase signal/noise; for brighter intensities, 1 trial sufficed. The stimulus monitor trace is shown at the bottom, with light intensities increasing from bottom to top (indicated on the left in units of R*/rod/s). (C) CAPs (data indicate the mean ± SD) of WT (left, black) and Opa1R290Q/+ (right, blue) retinas. Responses of each retina were normalized to its maximum value at each light intensity. The normalized Opa1R290Q/+ traces (blue) were superimposed on the mean of the normalized WT traces (gray) for comparison. Shorter trials were used for dimmer stimuli, leading to a lack of error bars in some intervals. n = 7 WT and n = 7 Opa1R290Q/+ retinas per age group, except for n = 3 Opa1R290Q/+ retinas at the highest intensity. (D) Ratio of second and first ON peaks (ON P2/P1) from C. The mean ± SD is shown for WT (black) and Opa1R290Q/+ (blue). For the dimmest intensity, distinct peaks were not evident (average z score <10) and were therefore not included in the analyses. *P < 0.05 and ****P < 0.0001, by Mann-Whitney U test with bootstrapping (see Methods).