Axon degeneration sculpts neuronal connectivity patterns during development and isan early hallmark of several adult-onset neurodegenerative disorders. Substantial progress hasbeen made in identifying effector mechanisms driving axon fragmentation, but less is known aboutthe upstream signaling pathways that initiate this process. Here, we investigate the behavior of theactin-spectrin-based Membrane-associated Periodic Skeleton (MPS), and effects of actin andspectrin manipulations in sensory axon degeneration. We show that trophic deprivation (TD) ofmouse sensory neurons causes a rapid disassembly of the axonal MPS, which occurs prior toprotein loss and independently of caspase activation. Actin destabilization initiates TD-relatedretrograde signaling needed for degeneration; actin stabilization prevents MPS disassembly andretrograde signaling during TD. Depletion of bII-spectrin, a key component of the MPS, suppressesretrograde signaling and protects axons against degeneration. These data demonstrate structuralplasticity of the MPS and suggest its potential role in early steps of axon degeneration.

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