期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2012685118
关键词
delta 2 tubulin; mitochondria; DRG; bortezomib; axonopathy
资金
- Thompson Family Foundation (TFFI)
- TFFI
- NIH/National Institute on Aging [RO1AG050658]
- NIH/NINDS [R21NS120076]
- MIUR [PRIN-2017FJC3-004]
The study demonstrates that bortezomib affects microtubule stability in sensory neurons by promoting the accumulation of delta 2 tubulin, leading to peripheral neuropathy. Furthermore, it suggests a previously unrecognized pathogenic role for D2 in bortezomib-induced peripheral neuropathy, potentially through altered regulation of mitochondria motility.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据