Why are some neurons spared in neurodegeneration? Cellular subtype identity maintenance as a candidate...

Neurodegenerative diseases often damage some neuronal populations while sparing closely related neighbors. But instead of asking why some neurons die, should we be asking why some survive? This Essay proposes that a neuron's capacity to sustain the gene-regulatory machinery that maintains its subtype identity helps set the stress threshold beyond which recovery fails. The initiating insult may be metabolic, proteostatic, inflammatory, or arise from the surrounding tissue, but it is the cell's capacity for maintenance that will determine where the tipping point lies: above a critical level, the identity program recovers, whereas below it, regulatory loss becomes self-sustaining. Such a framing could have implications for how neuronal vulnerability to neurodegeneration is understood.