1. Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy
- Author
-
Giulia Fumagalli, Thomas H. Brannagan, Matthew Shorey, Melissa M. Rolls, Xiaoyi Qu, Wesley B. Grueber, Laura Monza, Kurenai Tanji, Grace Ji-eun Shin, Guido Cavaletti, Paola Alberti, Maria Elena Pero, Cristina Meregalli, Atul Kumar, Francesca Bartolini, Pero, M, Meregalli, C, Qu, X, Shin, G, Kumar, A, Shorey, M, Rolls, M, Tanji, K, Brannagan, T, Alberti, P, Fumagalli, G, Monza, L, Grueber, W, Cavaletti, G, Bartolini, F, Pero, M. E., Meregalli, C., Qu, X., Shin, G. J. -E., Kumar, A., Shorey, M., Rolls, M. M., Tanji, K., Brannagan, T. H., Alberti, P., Fumagalli, G., Monza, L., Grueber, W. B., Cavaletti, G., and Bartolini, F.
- Subjects
Sensory Receptor Cells ,Motility ,Antineoplastic Agents ,Mitochondrion ,Microtubules ,Mitochondrial Dynamics ,Bortezomib ,In vivo ,Microtubule ,Tubulin ,delta 2 tubulin, mitochondria, DRG, bortezomib, axonopathy ,Neoplasms ,medicine ,Animals ,Humans ,Cytoskeleton ,Zebrafish ,Multidisciplinary ,biology ,Axonopathy ,Chemistry ,Peripheral Nervous System Diseases ,Correction ,medicine.disease ,Axons ,Cell biology ,Mitochondria ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Peripheral neuropathy ,Drosophila melanogaster ,HEK293 Cells ,Delta 2 tubulin ,DRG ,Larva ,biology.protein ,medicine.drug - Abstract
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.
- Published
- 2021