Dingwall Caitlin B, Sasaki Yo, Strickland Amy, Wu Tong, Summers Daniel W, Bloom A Joseph, DiAntonio Aaron, Milbrandt Jeffrey
Department 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.
iScience. 2025 May 9;28(6):112626. doi: 10.1016/j.isci.2025.112626. eCollection 2025 Jun 20.
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.
程序性轴突退化（AxD）是许多神经退行性疾病的一个标志。在健康的轴突中，NMNAT2抑制AxD的关键执行者SARM1，以防止其耗尽NAD+并触发轴突破坏。AxD被认为受轴突内在机制控制，与外部因素无关。然而，利用由低表达NMNAT2突变导致慢性SARM1激活引起的人类神经病变疾病模型，我们证明神经元SARM1可在应激但仍存活的轴突因内在代谢衰竭而死亡之前很久就启动巨噬细胞介导的轴突清除。慢性SARM1激活会导致轴突肿胀并破坏磷脂酰丝氨酸（PS），PS是一种促进巨噬细胞吞噬轴突的信号分子。在该模型中，PS脂肪酶ABDH12的神经元表达可减少巨噬细胞激活、保护轴突并挽救运动功能，这表明PS失调是一种早期的依赖SARM1的轴突应激信号。阻断巨噬细胞介导的轴突清除可能是治疗依赖SARM1的神经疾病的一种有前景的治疗策略。
