Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves

Dingwall, C. B.; Sasaki, Y.; Strickland, A.; Summers, D.; Bloom, A. J.; DiAntonio, A.; Milbrandt, J.

doi:10.1101/2024.06.20.599919

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bioRxiv · 10.1101/2024.06.20.599919

Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves

Dingwall, C. B.·Sasaki, Y.·Strickland, A.·Summers, D.·Bloom, A. J.·DiAntonio, A.·Milbrandt, J.

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Abstract

Programmed axon degeneration (AxD) is a key feature of many neurodegenerative diseases. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of AxD, preventing it from initiating the rapid local NAD+ depletion and metabolic catastrophe that precipitates axon destruction. Because these components of the AxD pathway act within neurons, it was also assumed that the timetable of AxD was set strictly by a cell-intrinsic mechanism independent of neuron-extrinsic processes later activated by axon fragmentation. However, using a rare human disease model of neuropathy caused by hypomorphic NMNAT2 mutations and chronic SARM1 activation (sarmopathy), we demonstrated that neuronal SARM1 can initiate macrophage-mediated axon elimination long before stressed-but-viable axons would otherwise succumb to cell-intrinsic metabolic failure. Investigating potential SARM1-dependent signals that mediate macrophage recognition and/or engulfment of stressed-but-viable axons, we found that chronic SARM1 activation triggers axonal blebbing and dysregulation of phosphatidylserine (PS), a potent phagocyte immunomodulatory molecule. Neuronal expression of the phosphatidylserine lipase ABDH12 suppresses nerve macrophage activation, preserves motor axon integrity, and rescues motor function in this chronic sarmopathy model. We conclude that PS dysregulation is an early SARM1-dependent axonal stress signal, and that blockade of phagocytic recognition and engulfment of stressed-but-viable axons could be an attractive therapeutic target for management of neurological disorders involving SARM1 activation.

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Dingwall, C. B., Sasaki, Y., Strickland, A., Summers, D., Bloom, A. J., DiAntonio, A., Milbrandt, J.. 2024-06-25. Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves. https://doi.org/10.1101/2024.06.20.599919

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