SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/62027 |
| _version_ | 1811180594152865792 |
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| author | Yo Sasaki Hiroki Kakita Shunsuke Kubota Abdoulaye Sene Tae Jun Lee Norimitsu Ban Zhenyu Dong Joseph B Lin Sanford L Boye Aaron DiAntonio Shannon E Boye Rajendra S Apte Jeffrey Milbrandt |
| author_facet | Yo Sasaki Hiroki Kakita Shunsuke Kubota Abdoulaye Sene Tae Jun Lee Norimitsu Ban Zhenyu Dong Joseph B Lin Sanford L Boye Aaron DiAntonio Shannon E Boye Rajendra S Apte Jeffrey Milbrandt |
| author_sort | Yo Sasaki |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:05:59Z |
| format | Article |
| id | doaj.art-4275e0ca179049eabb78a4c6222a8885 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:05:59Z |
| publishDate | 2020-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4275e0ca179049eabb78a4c6222a88852022-12-22T04:32:39ZengeLife Sciences Publications LtdeLife2050-084X2020-10-01910.7554/eLife.62027SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degenerationYo Sasaki0https://orcid.org/0000-0003-0024-0031Hiroki Kakita1Shunsuke Kubota2Abdoulaye Sene3Tae Jun Lee4https://orcid.org/0000-0003-2699-2573Norimitsu Ban5Zhenyu Dong6Joseph B Lin7https://orcid.org/0000-0001-6667-9018Sanford L Boye8https://orcid.org/0000-0002-8803-9369Aaron DiAntonio9https://orcid.org/0000-0002-7262-0968Shannon E Boye10https://orcid.org/0000-0002-7312-3197Rajendra S Apte11https://orcid.org/0000-0003-2281-2336Jeffrey Milbrandt12Department of Genetics, Washington University School of Medicine, St. Louis, United StatesDepartment of Genetics, Washington University School of Medicine, St. Louis, United States; Department of Perinatal and Neonatal Medicine, Aichi Medical University, Aichi, JapanDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United StatesDepartment of Pediatrics, Powell Gene Therapy Center, Gainesville, United StatesDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, United States; Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, United StatesDepartment of Pediatrics, Division of Cellular and Molecular Therapy, Gainesville, United StatesDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United States; Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States; Department of Medicine, Washington University School of Medicine, St. Louis, United StatesDepartment of Genetics, Washington University School of Medicine, St. Louis, United States; Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, United StatesLeber 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.https://elifesciences.org/articles/62027retinal degenerationsNAD+SARM1NMNAT1LCA9axonal degeneration |
| spellingShingle | Yo Sasaki Hiroki Kakita Shunsuke Kubota Abdoulaye Sene Tae Jun Lee Norimitsu Ban Zhenyu Dong Joseph B Lin Sanford L Boye Aaron DiAntonio Shannon E Boye Rajendra S Apte Jeffrey Milbrandt SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration eLife retinal degenerations NAD+ SARM1 NMNAT1 LCA9 axonal degeneration |
| title | SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration |
| title_full | SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration |
| title_fullStr | SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration |
| title_full_unstemmed | SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration |
| title_short | SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration |
| title_sort | sarm1 depletion rescues nmnat1 dependent photoreceptor cell death and retinal degeneration |
| topic | retinal degenerations NAD+ SARM1 NMNAT1 LCA9 axonal degeneration |
| url | https://elifesciences.org/articles/62027 |
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