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bioRxiv · 10.1101/2022.12.23.521801

Membrane association is required for Stmn2-mediated axon protection

Thornburg-Suresh, E. J. C.·Richardson, J. E.·Summers, D. W.
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Abstract

Axon integrity is essential for functional connectivity in the nervous system. The degeneration of stressed or damaged axons is a common and sometimes initiating event in neurodegenerative disorders. Cellular factors that preserve axon integrity have an important influence on the fate of a damaged axon. Stathmin-2 (Stmn2) is an axon maintenance factor that is depleted in Amyotrophic Lateral Sclerosis and replenishment of Stmn2 can restore neurite outgrowth in diseased neurons. Stathmins have a well-documented role in microtubule dynamics during neurodevelopment, yet mechanisms responsible for Stmn2-mediated axon maintenance in injured neurons are not known. We demonstrate that membrane association of Stmn2 is critical for its axon-protective activity. Axonal enrichment of Stmn2 is driven by palmitoylation as well as tubulin interaction. We discover that another Stathmin, Stmn3, co-migrates with Stmn2-containing vesicles and undergoes regulated degradation through DLK-JNK signaling. The Stmn2 membrane targeting domain is both necessary and sufficient for localization to a specific vesicle population and confers sensitivity to DLK-dependent degradation. Our findings reveal a broader role for DLK in tuning the local abundance of palmitoylated Stathmins in axon segments. Moreover, palmitoylation is a critical component of Stathmin-mediated axon protection and defining the Stmn2-containing vesicle population will provide important clues toward mechanisms of axon maintenance.

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Thornburg-Suresh, E. J. C., Richardson, J. E., Summers, D. W.. 2022-12-23. Membrane association is required for Stmn2-mediated axon protection. https://doi.org/10.1101/2022.12.23.521801

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