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Relationship: 1834

Title

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Disturbance in microtubule dynamic instability leads to Impaired axonial transport

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Do not cite

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Evidence Collection Strategy

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Evidence Supporting this KER

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Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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. [1]

- 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). [2] 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). [3]

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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 [9], however, Nakata et. al found anterograde as well as retrograde transport to be inhibited [8].

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
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Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
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Domain of Applicability

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References

List of the literature that was cited for this KER description. More help

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.