Stage-Dependent Axon Transport of Proteasomes Contributes to Axon Development

• Retrogradely moving proteasomes are selectively elevated at the nascent axon
• Controlled proteasome transport establishes asymmetric proteostasis in neurons
• BDNF specifically promotes retrograde proteasomal transport via Ecm29 phosphorylation
• Phosphorylated Ecm29 facilitates proteasome-dynein association

SummaryAxon extension at the growing tip requires elevated local protein supply, with a capability sustainable over long axons in varying environments. The exact mechanisms, however, remain elusive. Here we report that axon-promoting factors elicited a retrograde transport-dependent removal of proteasomes from nascent axon terminals, thereby increasing protein stability at axon tips. Such an effect occurred through phosphorylation of a dynein-interacting proteasome adaptor protein Ecm29. During the transition from immature neurites to nascent axons in cultured hippocampal neurons, live-cell imaging revealed a significant increase of the retrograde axonal transport of fluorescently labeled 20S proteasomes. This retrograde proteasome transport depended on neuron stage and increased with axon lengths. Blockade of retrograde transport caused accumulation of proteasomes, reduction of axon growth, and attenuation of growth-associated Par6 at the axon tip of newly polarized neurons. Our results delineate a regulatory mechanism that controls proteasome abundance via preferential transport required for axon development in newborn neurons.

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