Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves
Summary: Programmed axon degeneration (AxD) is a hallmark of many neurodegenerative diseases. In healthy axons, NMNAT2 inhibits SARM1, the key executioner of AxD, to keep it from depleting NAD+ and triggering axon destruction. AxD was assumed to be governed by axon-intrinsic mechanisms, independent...
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Elsevier
2025-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225008879 |
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| author | Caitlin B. Dingwall Yo Sasaki Amy Strickland Tong Wu Daniel W. Summers A. Joseph Bloom Aaron DiAntonio Jeffrey Milbrandt |
| author_facet | Caitlin B. Dingwall Yo Sasaki Amy Strickland Tong Wu Daniel W. Summers A. Joseph Bloom Aaron DiAntonio Jeffrey Milbrandt |
| author_sort | Caitlin B. Dingwall |
| collection | DOAJ |
| description | Summary: Programmed axon degeneration (AxD) is a hallmark of many neurodegenerative diseases. In healthy axons, NMNAT2 inhibits SARM1, the key executioner of AxD, to keep it from depleting NAD+ and triggering axon destruction. AxD was assumed to be governed by axon-intrinsic mechanisms, independent of external factors. However, using a human disease model of neuropathy caused by hypomorphic NMNAT2 mutations resulting in chronic SARM1 activation, we demonstrated that neuronal SARM1 can initiate macrophage-mediated axon elimination long before stressed-but-viable axons would otherwise succumb to intrinsic metabolic failure. Chronic SARM1 activation causes axonal blebbing and disrupts phosphatidylserine (PS), a signaling molecule that promotes axon engulfment by macrophages. Neuronal expression of ABDH12, a PS lipase, reduces macrophage activation, preserves axons, and rescues motor function in this model, suggesting that PS dysregulation is an early SARM1-dependent axonal stress signal. Blocking macrophage-mediated axon elimination could be a promising therapeutic strategy for SARM1-dependent neurological diseases. |
| format | Article |
| id | doaj-art-2b758d1c846b4914aa7285d70fbd135d |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-2b758d1c846b4914aa7285d70fbd135d2025-08-20T02:26:09ZengElsevieriScience2589-00422025-06-0128611262610.1016/j.isci.2025.112626Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nervesCaitlin B. Dingwall0Yo Sasaki1Amy Strickland2Tong Wu3Daniel W. Summers4A. Joseph Bloom5Aaron DiAntonio6Jeffrey Milbrandt7Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Needleman Center for Neuro-metabolism and Axonal Therapeutics, St. Louis, MO 63110, USADepartment of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Needleman Center for Neuro-metabolism and Axonal Therapeutics, St. Louis, MO 63110, USA; Corresponding authorDepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Needleman Center for Neuro-metabolism and Axonal Therapeutics, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding authorSummary: Programmed axon degeneration (AxD) is a hallmark of many neurodegenerative diseases. In healthy axons, NMNAT2 inhibits SARM1, the key executioner of AxD, to keep it from depleting NAD+ and triggering axon destruction. AxD was assumed to be governed by axon-intrinsic mechanisms, independent of external factors. However, using a human disease model of neuropathy caused by hypomorphic NMNAT2 mutations resulting in chronic SARM1 activation, we demonstrated that neuronal SARM1 can initiate macrophage-mediated axon elimination long before stressed-but-viable axons would otherwise succumb to intrinsic metabolic failure. Chronic SARM1 activation causes axonal blebbing and disrupts phosphatidylserine (PS), a signaling molecule that promotes axon engulfment by macrophages. Neuronal expression of ABDH12, a PS lipase, reduces macrophage activation, preserves axons, and rescues motor function in this model, suggesting that PS dysregulation is an early SARM1-dependent axonal stress signal. Blocking macrophage-mediated axon elimination could be a promising therapeutic strategy for SARM1-dependent neurological diseases.http://www.sciencedirect.com/science/article/pii/S2589004225008879Molecular neuroscienceImmunology |
| spellingShingle | Caitlin B. Dingwall Yo Sasaki Amy Strickland Tong Wu Daniel W. Summers A. Joseph Bloom Aaron DiAntonio Jeffrey Milbrandt Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves iScience Molecular neuroscience Immunology |
| title | Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves |
| title_full | Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves |
| title_fullStr | Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves |
| title_full_unstemmed | Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves |
| title_short | Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves |
| title_sort | suppressing phagocyte activation by overexpressing the phosphatidylserine lipase abhd12 preserves sarmopathic nerves |
| topic | Molecular neuroscience Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225008879 |
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