SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy
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
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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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 3

Impaired RGC function in Opa1R290Q/+ mice as measured by ERG and VEP.

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Impaired RGC function in Opa1R290Q/+ mice as measured by ERG and VEP. (A...
(A) Diagram of recording setup: (1) subcutaneous recording electrode for VEP; (2) integrated LED stimulator and recording electrode for ERG; (3) snout reference electrode for VEPs. A ground electrode was inserted subcutaneously next to the tail (not shown). Diagram was created with BioRender. (B) Representative ERG and VEP traces from WT control mice. For flash ERG, the amplitudes of a-waves and b-waves were measured. For flash VEPs and pattern VEPs, the amplitude of N1 was measured. (C and D) Amplitudes of a-waves (C) and b-waves (D) of flash ERGs across ages. Each dot represents 1 animal. Amplitudes were normalized to WT average at each age. n = 15–17 WT and n = 16 Opa1R290Q/+ mice per age group. (E) Average flash ERG traces in 18MO animals. n = 15 WT and n = 16 Opa1R290Q/+ mice. (F) N1 amplitudes of flash VEP across age. Each dot represents 1 animal. Amplitudes were normalized to WT average at each age. n = 16–17 WT and n = 16 Opa1R290Q/+ mice per age group. (G) Average flash VEP traces in 18MO animals. n = 16 WT and n = 16 Opa1R290Q/+ mice. (H) N1 amplitudes of pattern VEP traces across ages. Each dot represents 1 animal. Amplitudes were normalized to the WT average at each age. n = 16–17 WT and n = 16 Opa1R290Q/+ mice per age group. (I) Average pattern VEP traces in 18MO animals. n = 16 WT and 16 Opa1R290Q/+ mice. Box plots (C, D, F, and H) denote minimum, first quartile, median, third quartile, and maximum values. Data in (E, G, and I) indicate the mean ± SEM. **P < 0.01 and ****P < 0.0001, by Mann-Whitney U test for each age group. All data indicate the mean ± SEM.