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Disturbance in microtubule dynamic instability leads to Impaired axonial transport
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Microtubule interacting drugs lead to peripheral neuropathy||adjacent||Not Specified||Not Specified||Marvin Martens (send email)||Under development: Not open for comment. Do not cite|
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). 
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 .
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.