Journal article
Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves
iScience, Vol.28(6), 112626
06/20/2025
DOI: 10.1016/j.isci.2025.112626
Abstract
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.
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•NMNAT2 deletion is sufficient to evoke chronic SARM1 activity in uninjured neurons•Chronic SARM1 activation triggers axon blebbing and phosphatidylserine exposure•Axon blebbing occurs in a sarmopathy mouse model•Neuronal ABHD12 overexpression in sarmopathy mouse model rescues motor neuropathy
Details
- Title: Subtitle
- Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves
- Creators
- Caitlin B. Dingwall - Washington University in St. Louis School of MedicineYo Sasaki - Washington University in St. Louis School of MedicineAmy Strickland - Washington University in St. Louis School of MedicineTong Wu - Washington University in St. Louis School of MedicineDaniel W. Summers - Washington University in St. Louis School of MedicineA. Joseph Bloom - Washington University in St. Louis School of MedicineAaron DiAntonio - Washington University in St. Louis School of MedicineJeffrey Milbrandt - Washington University in St. Louis School of Medicine
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.28(6), 112626
- DOI
- 10.1016/j.isci.2025.112626
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Publisher
- Elsevier Inc
- Grant note
- National Institutes of Health: R01NS087632, R01NS133348, R01NS119812, R01AG013730 Needleman Center for Neurometabolism and Axonal TherapeuticsBob and Signa Hermann Fund for Neuropathy Research
We thank Milbrandt and DiAntonio labs members for technical support and critical feedback on this manuscript. This work was supported by National Institutes of Health grants (R01NS087632 and R01NS133348 to J.M. and AD, R01NS119812 to J.M., A.D., and A.J.B., and R01AG013730 to J.M.) , the Needleman Center for Neurometabolism and Axonal Therapeutics, and the Bob and Signa Hermann Fund for Neuropathy Research.
- Language
- English
- Electronic publication date
- 05/09/2025
- Date published
- 06/20/2025
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984822960902771
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