1. SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration
- Author
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Aaron DiAntonio, Jeffrey Milbrandt, Sanford L. Boye, Norimitsu Ban, Tae Jun Lee, Shunsuke Kubota, Joseph Lin, Shannon E. Boye, Zhenyu Dong, Abdoulaye Sene, Yo Sasaki, Rajendra S. Apte, and Hiroki Kakita
- Subjects
Male ,0301 basic medicine ,Retinal degeneration ,SARM1 ,Mouse ,genetic structures ,Leber Congenital Amaurosis ,Degeneration (medical) ,Photoreceptor cell ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,NMNAT1 ,Nicotinamide-Nucleotide Adenylyltransferase ,Biology (General) ,0303 health sciences ,Cell Death ,General Neuroscience ,Retinal Degeneration ,Neurodegeneration ,General Medicine ,Phenotype ,LCA9 ,Cell biology ,medicine.anatomical_structure ,Medicine ,Female ,Axonal degeneration ,axonal degeneration ,Research Article ,Photoreceptor Cells, Vertebrate ,Retinopathy ,QH301-705.5 ,Science ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,NAD+ ,medicine ,Animals ,Humans ,030304 developmental biology ,Armadillo Domain Proteins ,General Immunology and Microbiology ,Retinal ,medicine.disease ,Leber congenital amaurosis ,eye diseases ,Cytoskeletal Proteins ,Disease Models, Animal ,030104 developmental biology ,chemistry ,retinal degenerations ,NAD+ kinase ,sense organs ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD + synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD + homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration. To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of photoreceptors, indicating these cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the photoreceptor, as conditional deletion of NMNAT1 in photoreceptors but not retinal pigment epithelial cells is sufficient to cause photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving photoreceptor cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway that is active in the setting of dysregulated NAD + metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.
- Published
- 2020