Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy.
Animals
Antineoplastic Agents
/ adverse effects
Axons
/ drug effects
Bortezomib
/ adverse effects
Disease Models, Animal
Drosophila melanogaster
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
HEK293 Cells
Humans
Larva
/ drug effects
Microtubules
/ drug effects
Mitochondria
/ drug effects
Mitochondrial Dynamics
/ drug effects
Neoplasms
/ drug therapy
Peripheral Nervous System Diseases
/ chemically induced
Sensory Receptor Cells
/ drug effects
Tubulin
/ genetics
Zebrafish
/ genetics
DRG
axonopathy
bortezomib
delta 2 tubulin
mitochondria
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
26 01 2021
26 01 2021
Historique:
entrez:
20
1
2021
pubmed:
21
1
2021
medline:
12
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33468672
pii: 2012685118
doi: 10.1073/pnas.2012685118
pmc: PMC7848563
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Tubulin
0
Bortezomib
69G8BD63PP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIA NIH HHS
ID : R01 AG050658
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS120076
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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