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Relationship: 1835


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Impaired axonial transport leads to Sensory axonal peripheral neuropathy

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 Arthur Author (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Defects in axonal transport are often suggested as a cause for peripheral neuropathies as the length-dependent, distal neurologic deficits observed in patients treated with taxol or other MSAs indicate an axonal loss comparable to dying-back neuropathies which are often linked to axonal transport defects. [1]

Mutations linked to axonal transport are known to cause Charcot-Marie-Tooth disease (peripheral neuropathy). A mutation in the gene coding for the motor protein kinesin 1B (KIF1B) was found in a CMT2A family. The transport of synaptic vesicles is mediated by KIF1B. [2]

Generated KIF1A mutant mice exhibited motor and sensory disturbances and transport of synaptic vesicle precursors was shown to be decreased in axons. [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

The KIF1B mutation, which was identified in a CMT2A family and proven to disturb axonal transport, was only found in this family and has never been confirmed. [2, 6]

KIF1A knockout mice were born alive but died within 24h after birth. All measurements of sensory and motor function, axonal degeneration and axonal transport were performed within these 24h. [3]

Neuropathy was induced in cats by administration of either acrylamide or triorthocresyl phosphate (TOCP). Neuropathic symptoms like axonal degeneration were detected in both acrylamide- as well as TOCP-induced neuropathic cats but axonal transport of proteins was shown to be disturbed only in acrylamide-induced neuropathic cats. [4]

Furthermore, only limited human in vivo evidence is available for KE1 and its relationship to the AO.

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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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

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


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

1. Rowinsky , E.K. and R.C. Donehower Paclitaxel (Taxol). New England Journal of Medicine, 1995. 332(15): p. 1004-1014.

2. Zhao, C., et al., Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell, 2001. 105(5): p. 587-97.

3. Yonekawa, Y., et al., Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice. The Journal of Cell Biology, 1998. 141(2): p. 431-441.

4. Pleasure, D.E., K.C. Mishler, and W.K. Engel, Axonal Transport of Proteins in Experimental Neuropathies. Science, 1969. 166(3904): p. 524-525.

5. Pérez-Ollé, R., et al., Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. Journal of Neurochemistry, 2005. 93(4): p. 861-874.

6. Pareyson, D., et al., Mitochondrial dynamics and inherited peripheral nerve diseases. Neuroscience Letters, 2015. 596(Supplement C): p. 66-77.