@article{c6fe0d4c09f844a0a2715e41369c78d5,
title = "SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration",
abstract = "Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.",
author = "Yo Sasaki and Hiroki Kakita and Shunsuke Kubota and Abdoulaye Sene and Lee, {Tae Jun} and Norimitsu Ban and Zhenyu Dong and Lin, {Joseph B.} and Boye, {Sanford L.} and {Di Antonio}, Aaron and Boye, {Shannon E.} and Apte, {Rajendra S.} and Jeffrey Milbrandt",
note = "Funding Information: We thank Amy Strickland, Nina Panchenko, Kimberly Kruse, Andrea Santeford, Rachel McClarney, Simburger Kelli, Timothy Fahrner, Neiner Alicia, and Cassidy Menendez for technical assistance. National Institute on Aging AG013730 Jeffrey Milbrandt National Institute of Neurological Disorders and Stroke NS087632 Aaron DiAntonio Jeffrey Milbrandt National Cancer Institute CA219866 Aaron DiAntonio Jeffrey Milbrandt National Eye Institute EY019287-06 Rajendra S Apte The Needleman Center for Neurometabolism and Axonal therapeutics Aaron DiAntonio Jeffrey Milbrandt Edward N. & Della L. Thome Memorial Foundation Rajendra S Apte Carl and Mildred Almen Reeves Foundation Rajendra S Apte Starr Foundation Rajendra S Apte Bill and Emily Kuzma Family Gift for Retinal Research Rajendra S Apte Jeffrey Fort Innovation Fund Rajendra S Apte Glenn Foundation for Medical Research Rajendra S Apte Research to Prevent Blindness, Inc Unrestricted Grant to the Department of Ophthalmology Rajendra S Apte Washington University in St. Louis Medical Scientist Training Program (NIH). T32 GM07200 Joseph B Lin Research to Prevent Blindness Nelson Trust Award Rajendra S Apte. Publisher Copyright: Copyright Sasaki et al.",
year = "2020",
month = oct,
doi = "10.7554/eLife.62027",
language = "English",
volume = "9",
pages = "1--19",
journal = "eLife",
issn = "2050-084X",
}