The degeneration of axons is the underlying pathological process of several neurological disorders. The Wallerian degeneration (Wld(S)) slow protein, which is primarily nuclear, markedly inhibits axonal degeneration. Contradictory models have been proposed to explain its mechanism, including a role in the nucleus, where it affects gene transcription, and roles outside the nucleus, where it regulates unknown effectors. To determine which pool of Wld(S) accounts for its axon-protective effects, we developed a strategy to control the spatial expression of proteins within neurons. This strategy couples a chemical genetic method to control protein stability with microfluidic culturing. Using neurons that are selectively deficient in Wld(S) in axons, we show that the axonal pool of Wld(S) is necessary for protection from axon degeneration. These results implicate an axonal pathway regulated by Wld(S) that controls axon degeneration.
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