Tenedini Federico Marcello, Yin Chang, Huang Jessica M, Dhiman Neena, Soba Peter, Parrish Jay Z
Department of Biology, University of Washington, Seattle, WA 98195.
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.
Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2422752122. doi: 10.1073/pnas.2422752122. Epub 2025 May 20.
Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors but the cellular and molecular bases for neurite length-dependent vulnerability of neurons to degeneration is largely unknown. Using sensory neurons as a model system we show that neuronal activation of the integrated stress response triggers expression of the Interleukin-6 homolog (), which is both necessary and sufficient for axon length-dependent degeneration of presynapses. Upd3 activates phagocytic glia, triggering phagocytic removal of presynapses preferentially on neurons with long axons, thus revealing an intrinsic axon length-dependent vulnerability to glial insult. Finally, we found that axon length-dependent presynapse loss in fly models of human NDDs utilized this pathway, requiring and glial expression of the phagocytic receptor draper. Our studies identify inflammatory cytokine signaling and glial phagocytosis as key determinants of axon length-dependent vulnerability, thus mechanistically linking these hallmarks of NDDs.
许多神经退行性疾病（NDDs）优先影响具有长轴突或复杂轴突分支的神经元，但神经元轴突长度依赖性易发生变性的细胞和分子基础在很大程度上尚不清楚。我们以感觉神经元作为模型系统，表明整合应激反应的神经元激活会触发白细胞介素-6同源物（Upd3）的表达，这对于突触前膜轴突长度依赖性变性既是必要的也是充分的。Upd3激活吞噬性神经胶质细胞，触发优先对长轴突神经元上的突触前膜进行吞噬清除，从而揭示了轴突长度依赖性对神经胶质损伤的内在易感性。最后，我们发现人类NDDs果蝇模型中轴突长度依赖性突触前膜丢失利用了这一途径，需要Upd3和吞噬受体draper的神经胶质细胞表达。我们的研究确定炎症细胞因子信号传导和神经胶质细胞吞噬作用是轴突长度依赖性易感性的关键决定因素，从而在机制上连接了NDDs的这些特征。
