Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons

Nathan P Staff, Jewel L. Podratz, Lukas Grassner, Miranda Bader, Justin Paz, Andrew M. Knight, Charles Lawrence Loprinzi, Eugenia D Trushina, Anthony John Windebank

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically-relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention.

Original languageEnglish (US)
Pages (from-to)124-131
Number of pages8
JournalNeuroToxicology
Volume39
DOIs
StatePublished - Dec 2013

Fingerprint

Axonal Transport
Spinal Ganglia
Microtubules
Polymerization
Neurons
Rats
Peripheral Nervous System Diseases
Tubulin
Proteasome Endopeptidase Complex
Bortezomib
Proteasome Inhibitors
Mitochondria
Diagnosis-Related Groups
Ubiquitination
Multiple Myeloma
Assays
Cell Survival
Cells

Keywords

  • Bortezomib
  • Chemotherapy-induced peripheral neuropathy
  • Dorsal root ganglia
  • Neurotoxicity
  • Peripheral neuropathy
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons. / Staff, Nathan P; Podratz, Jewel L.; Grassner, Lukas; Bader, Miranda; Paz, Justin; Knight, Andrew M.; Loprinzi, Charles Lawrence; Trushina, Eugenia D; Windebank, Anthony John.

In: NeuroToxicology, Vol. 39, 12.2013, p. 124-131.

Research output: Contribution to journalArticle

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