Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa, USA; Department of Biology, University of Iowa, Iowa City, Iowa, USA.
Department of Biology, University of Iowa, Iowa City, Iowa, USA.
J Biol Chem. 2023 Jul;299(7):104861. doi: 10.1016/j.jbc.2023.104861. Epub 2023 May 24.
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.
轴突完整性对于神经系统的功能连接至关重要。应激或受损轴突的退化是神经退行性疾病中常见且有时是起始事件。Stathmin-2（Stmn2）是一种轴突维持因子，在肌萎缩侧索硬化症中耗竭，Stmn2 的补充可以恢复患病神经元的神经突生长。然而，负责受损神经元中 Stmn2 介导的轴突维持的机制尚不清楚。我们使用原代感觉神经元来研究 Stmn2 在切断的轴突退化中的作用。我们发现 Stmn2 的膜结合对于其轴突保护活性至关重要。结构功能研究表明，Stmn2 的轴突富集是由棕榈酰化以及微管相互作用驱动的。通过活细胞成像，我们发现另一种 Stmn，Stmn3，与包含 Stmn2 的囊泡共迁移。我们还证明，Stmn3 通过双亮氨酸拉链激酶（DLK）-c-Jun N 末端激酶信号通路进行调节性降解。Stmn2 膜靶向结构域对于定位于特定囊泡群体是必需和充分的，并赋予对 DLK 依赖性降解的敏感性。我们的发现揭示了 DLK 在调节轴突段中棕榈酰化 Stmn 局部丰度方面的更广泛作用。此外，棕榈酰化是 Stmn 介导的轴突保护的关键组成部分，定义包含 Stmn2 的囊泡群体将为轴突维持的机制提供重要线索。
