Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy.
Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy.
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DOI：
10.1073/pnas.2012685118
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发表时间：
2021-01-26
影响因子：
11.1
通讯作者：
Bartolini F
中科院分区：
文献类型：
--
作者：
Pero ME;Meregalli C;Qu X;Shin GJ;Kumar A;Shorey M;Rolls MM;Tanji K;Brannagan TH;Alberti P;Fumagalli G;Monza L;Grueber WB;Cavaletti G;Bartolini F
化疗诱导的周围神经病变（CIPN）是一种使人衰弱的“垂死”神经病变，其特征是在接受化疗的癌症患者中观察到的远端至近端周围神经变性。CIPN的致病机制在很大程度上是未知的。我们报告说，在感觉神经元中，CIPN诱导药物硼替佐米引起轴突病变，并通过增加δ 2微管蛋白（D2）破坏线粒体运动，这是唯一不可逆的微管蛋白翻译后修饰和超稳定微管的标志物。这些数据为周围神经病变中与微管蛋白寿命增加相关的风险提供了新的范例，并表明靶向调节这种微管蛋白修饰的酶可能提供预防硼替佐米诱导的周围神经病变中观察到的轴突损伤的疗法。化疗引起的周围神经病变（CIPN）的发病机制知之甚少。在这里，我们报告说，CIPN引起的药物硼替佐米（Bort）促进δ 2微管蛋白（D2）的积累，同时影响微管的稳定性和动力学在体外和体内的感觉神经元和D2的积累是主要的无髓纤维和硼替佐米诱导的周围神经病变（BIPN）在人类的一个标志。此外，虽然D2过表达足以引起轴突病变并抑制线粒体运动，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，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，这表明看似无关的CIPN药物的致病机制可能会集中在微管蛋白损伤上。结果揭示了以前未被认识到的致病作用D2在BIPN，可能会发生通过改变线粒体运动的调节。
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating “dying back” neuropathy featuring a distal-to-proximal peripheral nerve degeneration seen in cancer patients undergoing chemotherapy. The pathogenenic mechanisms of CIPN are largely unknown. We report that in sensory neurons, the CIPN-inducing drug bortezomib caused axonopathy and disrupted mitochondria motility by increasing delta 2 tubulin (D2), the only irreversible tubulin posttranslational modification and a marker of hyper-stable microtubules. These data provide a new paradigm for the risk associated with enhanced tubulin longevity in peripheral neuropathy and suggest that targeting the enzymes regulating this tubulin modification may provide therapies that prevent the axonal injury observed in bortezomib-induced peripheral neuropathy. 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.
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