PUBLICATION
Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy
- Authors
- Pero, M.E., Meregalli, C., Qu, X., Shin, G.J., Kumar, A., Shorey, M., Rolls, M.M., Tanji, K., Brannagan, T.H., Alberti, P., Fumagalli, G., Monza, L., Grueber, W.B., Cavaletti, G., Bartolini, F.
- ID
- ZDB-PUB-210612-8
- Date
- 2021
- Source
- Proceedings of the National Academy of Sciences of the United States of America 118(4): (Journal)
- Registered Authors
- Keywords
- DRG, axonopathy, bortezomib, delta 2 tubulin, mitochondria
- MeSH Terms
-
- Neoplasms/drug therapy*
- Neoplasms/genetics
- Neoplasms/pathology
- Mitochondria/drug effects
- Mitochondria/genetics
- Bortezomib/adverse effects*
- Mitochondrial Dynamics/drug effects
- Mitochondrial Dynamics/genetics
- Humans
- Peripheral Nervous System Diseases/chemically induced
- Peripheral Nervous System Diseases/genetics*
- Peripheral Nervous System Diseases/pathology
- Zebrafish/genetics
- Antineoplastic Agents/adverse effects
- Sensory Receptor Cells/drug effects
- Sensory Receptor Cells/pathology
- Tubulin/genetics*
- Animals
- Axons/drug effects
- Axons/pathology
- Drosophila melanogaster/genetics
- Microtubules/drug effects
- Microtubules/genetics
- Larva/drug effects
- Larva/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Disease Models, Animal
- HEK293 Cells
- PubMed
- 33468672 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Pero, M.E., Meregalli, C., Qu, X., Shin, G.J., Kumar, A., Shorey, M., Rolls, M.M., Tanji, K., Brannagan, T.H., Alberti, P., Fumagalli, G., Monza, L., Grueber, W.B., Cavaletti, G., Bartolini, F. (2021) Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy. Proceedings of the National Academy of Sciences of the United States of America. 118(4).
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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-271 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
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Orthology
Engineered Foreign Genes
Mapping