Sterile alpha and TIR motif containing 1 (SARM1) is an inducible NADase that localizes to mitochondria throughout neurons and senses metabolic changes that occur after injury. Minimal proteomic changes are observed upon either SARM1 depletion or activation, suggesting that SARM1 does not exert broad effects on neuronal protein homeostasis. However, whether SARM1 activation occurs throughout the neuron in response to injury and cell stress remains largely unknown. Using a semiautomated imaging pipeline and a custom-built deep learning scoring algorithm, we studied degeneration in both mixed-sex mouse primary cortical neurons and male human-induced pluripotent stem cell-derived cortical neurons in response to a number of different stressors. We show that SARM1 activation is differentially restricted to specific neuronal compartments depending on the stressor. Cortical neurons undergo SARM1-dependent axon degeneration after mechanical transection, and SARM1 activation is limited to the axonal compartment distal to the injury site. However, global SARM1 activation following vacor treatment causes both cell body and axon degeneration. Context-specific stressors, such as microtubule dysfunction and mitochondrial stress, induce axonal SARM1 activation leading to SARM1-dependent axon degeneration and SARM1-independent cell body death. Our data reveal that compartment-specific SARM1–mediated death signaling is dependent on the type of injury and cellular stressor.

含有不育 α 和 TIR 基序 1 (SARM1) 是一种诱导型 NAD 酶，定位于整个神经元的线粒体，并感知损伤后发生的代谢变化。在 SARM1 耗尽或激活时观察到最小的蛋白质组变化，表明 SARM1 不会对神经元蛋白质稳态产生广泛影响。然而，SARM1 激活是否发生在整个神经元中以响应损伤和细胞应激仍然很大程度上未知。使用半自动成像流程和定制的深度学习评分算法，我们研究了混合性别小鼠原代皮质神经元和男性人类诱导的多能干细胞衍生的皮质神经元响应多种不同压力源的变性。我们发现，SARM1 的激活根据应激源的不同而不同地局限于特定的神经元区室。机械横断后，皮质神经元经历 SARM1 依赖性轴突变性，并且 SARM1 激活仅限于损伤部位远端的轴突室。然而，vacor 治疗后全局 SARM1 激活会导致细胞体和轴突变性。特定环境的应激源，例如微管功能障碍和线粒体应激，会诱导轴突 SARM1 激活，导致 SARM1 依赖性轴突变性和 SARM1 独立细胞体死亡。我们的数据表明，区室特异性 SARM1 介导的死亡信号传导取决于损伤类型和细胞应激源。