Context-Specific Stress Causes Compartmentalized SARM1 Activation and Local Degeneration in Cortical Neurons

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Sterile alpha and TIR motif containing 1 (SARM1) is an inducible NADase in neurons, sensing metabolic changes post-injury.
• SARM1's role in broad neuronal protein homeostasis is minimal, but its activation patterns after injury and stress are not fully understood.

Purpose of the Study:

• To investigate the spatial activation of SARM1 within neurons in response to various injury and stress conditions.
• To determine if SARM1 activation is globally distributed or compartment-specific.

Main Methods:

• Utilized a semiautomated imaging pipeline and a deep learning algorithm to analyze neuronal degeneration.
• Studied both mouse primary cortical neurons and human induced pluripotent stem cell-derived cortical neurons under different stressors.
• Examined SARM1 activation in response to mechanical transection, vacor treatment, microtubule dysfunction, and mitochondrial stress.

Main Results:

• SARM1 activation is differentially restricted to specific neuronal compartments based on the stressor.
• Mechanical transection leads to SARM1-dependent axon degeneration with activation localized distally.
• Vacor treatment causes global SARM1 activation and degeneration of both cell body and axon.
• Microtubule or mitochondrial stress induces axonal SARM1 activation, causing axon degeneration but not cell body death.

Conclusions:

• Neuronal death signaling via SARM1 is compartment-specific and contingent on the nature of the injury or stressor.
• SARM1 activation is not uniform throughout the neuron but is precisely localized depending on the context.
• These findings elucidate the context-dependent role of SARM1 in neuronal degeneration pathways.