Zuckerman Mind Brain Behavior Institute, Jerome L. Greene Science Center, Columbia University, New York, NY 10027;
Pathology & Cell Biology, Columbia University, New York, NY 10032.
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2006050118.
Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.
化疗引起的周围神经病（CIPN）是癌症治疗的一种主要副作用，临床上尚无预防或治疗方法。CIPN 通常影响无髓鞘伤害感受器末端。尽管 CIPN 很常见，但导致 CIPN 的分子和细胞机制仍知之甚少。在这里，我们使用遗传上可操作的模型和从成年小鼠分离的初级感觉神经元来研究 CIPN 的潜在机制，并确定保护途径。我们发现，紫杉醇慢性处理幼虫会导致伤害感受器神经元的退化和分支模式改变，并降低热伤害感受反应。我们进一步发现，整合素在伤害感受器神经元中的特异性过表达，已知整合素在几个系统中支持神经元的维持，可对紫杉醇诱导的细胞和行为表型提供保护。活细胞成像和超分辨率方法提供了证据，表明紫杉醇处理会引起与整合素介导的内体运输改变一致的细胞变化。紫杉醇诱导的循环内体变化先于伤害感受器神经元树突的形态退化，而过表达整合素可以预防这种退化。我们使用原代背根神经节（DRG）神经元培养物来测试整合素介导的保护作用的保守性。我们发现，转导人整合素β亚基 1 也可以防止紫杉醇处理后神经元的退化。此外，紫杉醇处理的小鼠 DRG 神经元中内源性表面整合素水平降低，这表明紫杉醇破坏了脊椎动物感觉神经元中的循环。总之，我们的研究支持紫杉醇诱导的整合素运输失调的保守机制，以及通过恢复神经元与细胞外环境的相互作用来拮抗紫杉醇诱导的感觉神经元毒性的治疗潜力。
