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
  • Peripheral Nervous System Diseases/chemically induced
  • Peripheral Nervous System Diseases/genetics*
  • Peripheral Nervous System Diseases/pathology
  • Gene Expression Regulation, Neoplastic/drug effects
  • Mitochondrial Dynamics/drug effects
  • Mitochondrial Dynamics/genetics
  • Neoplasms/drug therapy*
  • Neoplasms/genetics
  • Neoplasms/pathology
  • Animals
  • Sensory Receptor Cells/drug effects
  • Sensory Receptor Cells/pathology
  • Zebrafish/genetics
  • Disease Models, Animal
  • Antineoplastic Agents/adverse effects
  • Drosophila melanogaster/genetics
  • HEK293 Cells
  • Axons/drug effects
  • Axons/pathology
  • Tubulin/genetics*
  • Mitochondria/drug effects
  • Mitochondria/genetics
  • Bortezomib/adverse effects*
  • Microtubules/drug effects
  • Microtubules/genetics
  • Humans
  • Larva/drug effects
  • Larva/genetics
(all 28)
PubMed
33468672 Full text @ Proc. Natl. Acad. Sci. USA
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
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
mitfaw2/w2; mpv17a9/a9; la207Tg/+; psu1Tg/+chemical treatment by environment: bortezomibAdult
mitfaw2/w2; mpv17a9/a9; la207Tg/+; psu1Tg/+chemical treatment by environment: bortezomibAdult
1 - 2 of 2
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    la207TgTransgenic Insertion
      psu1TgTransgenic Insertion
        w2
          		Point Mutation
          1 - 4 of 4
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          Human Disease / Model
          Human Disease Fish Conditions Evidence
          peripheral nervous system diseaseTAS
          1 - 1 of 1
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          Sequence Targeting Reagents
          No data available
          Fish
          Fish
          mitfaw2/w2; mpv17a9/a9; la207Tg/+; psu1Tg/+
          1 - 1 of 1
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          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          GFPEFGGFP
          mCherryEFGmCherry
          1 - 2 of 2
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          Mapping
          No data available
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          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).