Microtubules, Membranes, and Movement: New Roles for Stathmin-2 in Axon Integrity.

Neurons establish functional connections responsible for how we perceive and react to the world around us. Communication from a neuron to its target cell occurs through a long projection called an axon. Axon distances can exceed 1 m in length in humans and require a dynamic microtubule cytoskeleton for growth during development and maintenance in adulthood. Stathmins are microtubule-associated proteins that function as relays between kinase signaling and microtubule polymerization. In this review, we describe the prolific role of Stathmins in microtubule homeostasis with an emphasis on emerging roles for Stathmin-2 (Stmn2) in axon integrity and neurodegeneration. Stmn2 levels are altered in Amyotrophic Lateral Sclerosis and loss of Stmn2 provokes motor and sensory neuropathies. There is growing potential for employing Stmn2 as a disease biomarker or even a therapeutic target. Meeting this potential requires a mechanistic understanding of emerging complexity in Stmn2 function. In particular, Stmn2 palmitoylation has a surprising contribution to axon maintenance through undefined mechanisms linking membrane association, tubulin interaction, and axon transport. Exploring these connections will reveal new insight on neuronal cell biology and novel opportunities for disease intervention.

The Stathmin-2 membrane-targeting domain is required for axon protection and regulated degradation by DLK signaling.

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. 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. However, mechanisms responsible for Stmn2-mediated axon maintenance in injured neurons are not known. We used primary sensory neurons to interrogate the role of Stmn2 in the degeneration of severed axons. We discover that membrane association of Stmn2 is critical for its axon-protective activity. Structure-function studies revealed that axonal enrichment of Stmn2 is driven by palmitoylation as well as tubulin interaction. Using live imaging, we discover that another Stmn, Stmn3, comigrates with Stmn2-containing vesicles. We also demonstrate that Stmn3 undergoes regulated degradation through dual leucine zipper kinase (DLK)-c-Jun N-terminal kinase 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 Stmns in axon segments. Moreover, palmitoylation is a critical component of Stmn-mediated axon protection, and defining the Stmn2-containing vesicle population will provide important clues toward mechanisms of axon maintenance.