Upstream eventDisturbance in microtubule dynamic instability
Impaired axonial transport
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Microtubule interacting drugs lead to peripheral neuropathy||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
Evidence Supporting this KER
An impairment in axonal transport leads to an inadequate supply of the neuronal periphery.
Mutations linked to microtubules are known to cause peripheral neuropathies:
- Mutations in the TUBB3 coding gene are known to cause congenital fibrosis of the extraocular muscle type 3 (CFEOM3) and also lead to later-onset peripheral neuropathies. Microtubules were shown to be more stable and changes to microtubule dynamic instability were evidenced. Furthermore, Kif21a exhibits impaired interaction with microtubules thereby influencing axonal transport. 
- Patients suffering from Charcot-Marie-Tooth (CMT) neuropathy exhibit length-dependend degeneration of peripheral nerves. CMT type 2 is associated with axonal degeneration leading to reduced action potentials. CMT2F is caused by a mutation in the gene coding for heat shock protein B1 (HSPB1).  Heat shock proteins can stabilize or protect the structure of other proteins and specifically mutated HSPB1 was shown to bind to and stabilize microtubules and disturb microtubule dynamic instability (see below). 
- Enhanced binding to microtubules was documented for mutated HSPB1 (measured by immunoprecipitation, cosedimentation assay, KD determination (SPR)). Furthermore, mutated HSPB1 was shown to stabilize microtubules (measured by cold-induced depolymerization assay, Nocodazole approach, cell migration (scratch) assay) and thereby disrupt microtubule dynamic instability (measured by tracking of TUBB3-GFP microtubules and in HSPB1 transgenic mice). 
- TUBB3 mutations were shown to change binding of KIFs to microtubules and thereby disrupt axonal transport of vesicles and mitochondria in cells derived from the peripheral nervous system. 
- Taxol, known to disrupt microtubule dynamic instability [5, 6], was proven to decrease transport of horseradish peroxidase in dorsal root ganglia neurons (and also less microtubule crosslinks were observed) Intact axonal transport can be re-gained after taxol wash-out (1 day treatment, 2 days wash-out). .
- It was shown that Taxol inhibits anterograde fast (and retrograde) axonal transport in rat sciatic nerves  and anterograde transport in SK-N-SH human neuroblastoma cells and mice sciatic nerves .
- Taxol, ixabepilone, vincristine and eribulin, all of which are known to suppress microtubule dynamic instability, were proven to have inhibitory effects on anterograde fast axonal transport in isolated squid axoplasm. 
- Posttranslational modifications of tubulin were shown to increase upon Taxol treatment and an increase in the stabile fraction of microtubules was observed. In the same time scale, also KIF1 accumulation was observed indicating disruption of axonal transport. 
Uncertainties and Inconsistencies
Quantitative data illustrating a causal relationship between KE1 and the KE2 is not available.
Most studies in the literature only deal with the direct link of ‘known MSAs’ to KE2 ‘impaired axonal transport’. The disturbance in microtubule dynamic instability was rarely proven in studies using MSAs to investigate their effects on axonal transport. [8-10] Concentration- and/or time-dependency was investigated only in some of the studies. [7, 9-11]
Results of transport experiments are sometimes contradicting regarding the inhibition of retrograde axonal transport upon Taxol treatment, e.g. Smith et. al claims that only anterograde transport is inhibited , however, Nakata et. al found anterograde as well as retrograde transport to be inhibited .
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
1. Tischfield, M.A., et al., Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell, 2010. 140(1): p. 74-87.
2. Ismailov, S.M., et al., A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. Eur J Hum Genet, 2001. 9(8): p. 646-50.
3. Almeida-Souza, L., et al., Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy. J Neurosci, 2011. 31(43): p. 15320-8.
4. Niwa, S., H. Takahashi, and N. Hirokawa, beta-Tubulin mutations that cause severe neuropathies disrupt axonal transport. Embo j, 2013. 32(10): p. 1352-64.
5. Derry, W.B., L. Wilson, and M.A. Jordan, Substoichiometric Binding of Taxol Suppresses Microtubule Dynamics. Biochemistry, 1995. 34(7): p. 2203-2211.
6. Witte, H., D. Neukirchen, and F. Bradke, Microtubule stabilization specifies initial neuronal polarization. The Journal of Cell Biology, 2008. 180(3): p. 619-632.
7. Theiss, C. and K. Meller, Taxol impairs anterograde axonal transport of microinjected horseradish peroxidase in dorsal root ganglia neurons in vitro. Cell Tissue Res, 2000. 299(2): p. 213-24.
8. Nakata, T. and H. Yorifuji, Morphological evidence of the inhibitory effect of taxol on the fast axonal transport. Neuroscience Research, 1999. 35(2): p. 113-122.
9. Smith, J.A., et al., Structural Basis for Induction of Peripheral Neuropathy by Microtubule-Targeting Cancer Drugs. Cancer Research, 2016. 76(17): p. 5115-5123.
10. LaPointe, N.E., et al., Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology, 2013. 37: p. 231-9.
11. Hammond, J.W., et al., Posttranslational modifications of tubulin and the polarized transport of kinesin-1 in neurons. Mol Biol Cell, 2010. 21(4): p. 572-83.