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

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-05-09 DOI:10.1016/j.isci.2025.112626

Caitlin B. Dingwall , Yo Sasaki , Amy Strickland , Tong Wu , Daniel W. Summers , A. Joseph Bloom , Aaron DiAntonio , Jeffrey Milbrandt

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引用次数: 0

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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通过过表达磷脂酰丝氨酸脂肪酶ABHD12抑制吞噬细胞活化可保护肉瘤神经

程序性轴突变性（axon degeneration, AxD）是许多神经退行性疾病的标志。在健康的轴突中，NMNAT2抑制SARM1 （AxD的关键执行者），以防止其消耗NAD+并引发轴突破坏。AxD被认为是由轴突内在机制控制的，独立于外部因素。然而，利用由NMNAT2亚型突变导致的慢性SARM1激活引起的神经病变的人类疾病模型，我们证明了神经元SARM1可以在应激但存活的轴突屈服于内在代谢衰竭之前很久就启动巨噬细胞介导的轴突消除。慢性SARM1激活会引起轴突泡并破坏磷脂酰丝氨酸（PS），这是一种促进巨噬细胞吞噬轴突的信号分子。在该模型中，神经元表达ABDH12（一种PS脂肪酶）可降低巨噬细胞活化、保存轴突并恢复运动功能，提示PS失调是早期依赖sarm1的轴突应激信号。阻断巨噬细胞介导的轴突消除可能是一种有希望的治疗sarm1依赖性神经系统疾病的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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