[Damage response mechanisms for evading neurodegeneration: mitochondrial supply driven by logistics gate disassembly]

Mature neurons are highly vulnerable to trauma and neurodegenerative diseases. Conversely, certain peripheral neurons exhibit remarkable survival and regenerative capacities by synchronously activating damage responses to undergo a transient "rejuvenation." Identifying and elucidating these unresolved mechanisms is essential for understanding disease pathogenesis and developing fundamental therapies. Because these responses are driven by complex intercellular interactions, in vivo investigations are indispensable. To address this, we developed the Atf3:BAC Tg mice, a powerful tool that enables damaged neuron-specific genetic manipulation coupled with mitochondrial visualization. Tracking mitochondrial dynamics-which sensitively reflect neuronal states-revealed a novel damage response: injured motor neurons actively disassemble the axon initial segment (AIS), a structural hallmark of mature neurons, via the proteasome to evade axonal degeneration. The AIS functions as a logistical gate restricting axonal transport between the soma and the axon. Strikingly, dismantling this gate allows healthy mitochondria to surge from the soma into the distal axon, successfully preventing energy depletion. In contrast, in amyotrophic lateral sclerosis (ALS) motor neurons, this disassembly switch malfunctions from the early stages of the disease; the gate remains closed under pathological insults, leading to energetic starvation and subsequent degeneration. Intriguingly, ALS-resistant sensory neurons inherently lack this logistical gate, allowing unrestricted mitochondrial supply to axons even under proteasomal dysfunction. This review outlines these cutting-edge findings and introduces the forefront of fundamental research aiming to uncover the pathogenesis of neurodegenerative diseases through the lens of neuronal damage responses.