Universität zu Köln

Bobylev, Ilja, Joshi, Abhijeet R., Barham, Mohammed, Ritter, Christian, Neiss, Wolfram F., Hoke, Ahmet and Lehmann, Helmar C. (2015). Paclitaxel inhibits mRNA transport in axons. Neurobiol. Dis., 82. S. 321 - 332. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1095-953X

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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 mitochondria] 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. (C) 2015 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bobylev, Ilja UNSPECIFIED UNSPECIFIED UNSPECIFIED Joshi, Abhijeet R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Barham, Mohammed UNSPECIFIED UNSPECIFIED UNSPECIFIED Ritter, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Neiss, Wolfram F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoke, Ahmet UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmann, Helmar C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-392230
DOI:	10.1016/j.nbd.2015.07.006
Journal or Publication Title:	Neurobiol. Dis.
Volume:	82
Page Range:	S. 321 - 332
Date:	2015
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1095-953X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PAINFUL PERIPHERAL NEUROPATHY; MITOCHONDRIAL DYSFUNCTION; NEURODEGENERATIVE DISEASES; SENSORY NEUROPATHY; OXIDATIVE STRESS; NERVE; FISSION; FUSION; CELLS; RAT Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39223