The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.

化疗引起的周围神经病变 (CIPN) 的发病机制知之甚少。在这里，我们报告导致 CI​​PN 的药物硼替佐米 (Bort) 促进 delta 2 微管蛋白 (D2) 积累，同时影响体外和体内感觉神经元的微管稳定性和动力学，并且 D2 的积累主要在无髓纤维和一个标志硼替佐米诱导的人类周围神经病变 (BIPN)。此外，虽然 D2 过表达足以引起轴突病并抑制线粒体运动，但 D2 水平的降低减轻了由 Bort 诱导的轴突变性和线粒体运动的丧失。总之，我们的数据表明，Bort 是一种结构上与微管蛋白毒物无关的化合物，在体外、体内和人体组织中影响感觉神经元中的微管蛋白细胞骨架，表明看似无关的CIPN药物的致病机制可能集中在微管蛋白损伤上。结果揭示了 D2 在 BIPN 中以前未被认识到的致病作用，这可能通过改变线粒体运动的调节而发生。