Paclitaxel inhibits mRNA transport in axons

Neurobiol Dis. 2015 Oct;82:321-331. doi: 10.1016/j.nbd.2015.07.006. Epub 2015 Jul 15.

Abstract

Paclitaxel is an integral component of solid tumor treatment. This chemotherapeutic agent provokes an often irreversible peripheral sensory neuropathy with pathological features of distal axonal degeneration. Current pathological concepts assume that polymerization of axonal microtubules and mitochondrial dysfunction contributes to the development of paclitaxel-induced peripheral neuropathy. The relationship, however, between microtubule stabilization, mitotoxicity and axonal degeneration is still not completely understood. To explore the function of axonal mitochondria we treated transgenic mice that harbor cyan fluorescent protein (CFP)-labeled neuronal mitochondria with repeated doses of paclitaxel and assessed neuropathic changes by nerve conduction and histological studies. In addition, mitochondrial content and morphology was determined by ex vivo imaging of axons containing CFP-labeled mitochondria. Using quantitative RT-PCR and fluorescence-labeled mRNA we determined axonal mRNA transport of nuclear encoded mitochondrial proteins. Prolonged treatment with high doses of paclitaxel-induced a predominant sensory neuropathy in mice. Although mitochondrial velocity in axons per se was not altered, we observed significant changes in mitochondrial morphology, suggesting that paclitaxel treatment impairs the dynamics of axonal mitochondria. These changes were caused by decreased levels of nuclear encoded mRNA, including the mitochondrial fusion/fission machinery. Moreover, impaired axonal mRNA transport in vitro resulted in mitochondrial dysfunction and subsequent axonal degeneration. Taken together, our experiments provide evidence that disrupted axonal transport of nuclear derived mRNA plays a crucial role in the pathogenesis of paclitaxel-induced sensory neuropathy.

Keywords: Axonal transport; Chemotherapy; Microtubule; Mitochondria; Neuropathy; Taxol; Toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axonal Transport / drug effects*
  • Axonal Transport / physiology
  • Axons / drug effects*
  • Axons / metabolism*
  • Axons / ultrastructure
  • Cells, Cultured
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hindlimb / innervation
  • Hindlimb / pathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neural Conduction / drug effects
  • Neural Conduction / physiology
  • Paclitaxel / pharmacology*
  • RNA, Messenger / metabolism*
  • Rats, Wistar
  • Schwann Cells / drug effects
  • Schwann Cells / metabolism
  • Schwann Cells / ultrastructure
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / ultrastructure
  • Skin / innervation
  • Skin / pathology
  • Tibial Nerve / drug effects
  • Tibial Nerve / metabolism
  • Tibial Nerve / ultrastructure
  • Tubulin Modulators / pharmacology*

Substances

  • Cyan Fluorescent Protein
  • RNA, Messenger
  • Tubulin Modulators
  • Green Fluorescent Proteins
  • Paclitaxel