title: Paclitaxel inhibits mRNA transport in axons.
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.
authors.affiliation: Department of Neurology, University Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Ilja
authors.initials: I
authors.lastname: Bobylev
authors.affiliation: Department of Neurology, University Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Abhijeet R
authors.initials: AR
authors.lastname: Joshi
authors.affiliation: Department of Anatomy I, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Barham
authors.affiliation: Department of Neurology, University Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ritter
authors.affiliation: Department of Anatomy I, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Wolfram F
authors.initials: WF
authors.lastname: Neiss
authors.affiliation: Department of Neurology, Johns Hopkins Hospital, Baltimore, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Höke
authors.affiliation: Department of Neurology, University Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany. Electronic address: helmar.lehmann@uk-koeln.de.
authors.forename: Helmar C
authors.initials: HC
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D001369:Axons / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb / Q000294:innervation / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D017208:Rats, Wistar; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D012867:Skin / Q000294:innervation / Q000473:pathology; D013979:Tibial Nerve / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C485182:Cyan Fluorescent Protein; D012333:RNA, Messenger; D050257:Tubulin Modulators; D049452:Green Fluorescent Proteins; D017239:Paclitaxel
keywords: Axonal transport; Chemotherapy; Microtubule; Mitochondria; Neuropathy; Taxol; Toxicity