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Article

SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration

1
Department of Genetics, The School of Genetics and Microbiology, Trinity College Dublin, D02 VF25 Dublin, Ireland
2
The Research Foundation, Royal Victoria Eye and Ear Hospital, D02 XK51 Dublin, Ireland
3
Trinity Biomedical Sciences Institute, The School of Biochemistry and Immunology, Trinity College Dublin, D02 R590 Dublin, Ireland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Takuji Kurimoto
Int. J. Mol. Sci. 2022, 23(3), 1606; https://doi.org/10.3390/ijms23031606
Received: 27 October 2021 / Revised: 21 January 2022 / Accepted: 26 January 2022 / Published: 30 January 2022
The challenge of developing gene therapies for genetic forms of blindness is heightened by the heterogeneity of these conditions. However, mechanistic commonalities indicate key pathways that may be targeted in a gene-independent approach. Mitochondrial dysfunction and axon degeneration are common features of many neurodegenerative conditions including retinal degenerations. Here we explore the neuroprotective effect afforded by the absence of sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a prodegenerative NADase, in a rotenone-induced mouse model of retinal ganglion cell loss and visual dysfunction. Sarm1 knockout mice retain visual function after rotenone insult, displaying preservation of photopic negative response following rotenone treatment in addition to significantly higher optokinetic response measurements than wild type mice following rotenone. Protection of spatial vision is sustained over time in both sexes and is accompanied by increased RGC survival and additionally preservation of axonal density in optic nerves of Sarm1−/− mice insulted with rotenone. Primary fibroblasts extracted from Sarm1−/− mice demonstrate an increased oxygen consumption rate relative to those from wild type mice, with significantly higher basal, maximal and spare respiratory capacity. Collectively, our data indicate that Sarm1 ablation increases mitochondrial bioenergetics and confers histological and functional protection in vivo in the mouse retina against mitochondrial dysfunction, a hallmark of many neurodegenerative conditions including a variety of ocular disorders. View Full-Text
Keywords: axon degeneration; sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1); NAD+; NADase; retinal degeneration axon degeneration; sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1); NAD+; NADase; retinal degeneration
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MDPI and ACS Style

Finnegan, L.K.; Chadderton, N.; Kenna, P.F.; Palfi, A.; Carty, M.; Bowie, A.G.; Millington-Ward, S.; Farrar, G.J. SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration. Int. J. Mol. Sci. 2022, 23, 1606. https://doi.org/10.3390/ijms23031606

AMA Style

Finnegan LK, Chadderton N, Kenna PF, Palfi A, Carty M, Bowie AG, Millington-Ward S, Farrar GJ. SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration. International Journal of Molecular Sciences. 2022; 23(3):1606. https://doi.org/10.3390/ijms23031606

Chicago/Turabian Style

Finnegan, Laura K., Naomi Chadderton, Paul F. Kenna, Arpad Palfi, Michael Carty, Andrew G. Bowie, Sophia Millington-Ward, and G. J. Farrar. 2022. "SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration" International Journal of Molecular Sciences 23, no. 3: 1606. https://doi.org/10.3390/ijms23031606

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