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Event: 1582

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Impaired axonial transport

Short name

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Microtubule interacting drugs lead to peripheral neuropathy	KeyEvent	Marvin Martens (send email)	Under development: Not open for comment. Do not cite
tau-AOP	KeyEvent	Erwin L Roggen (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The cytoskeleton plays an important role in neurons as it is required for the typical neuronal architecture of one long process, the axon, and several shorter dendrites. [1] Furthermore, the intact cytoskeleton is also of high importance as it is needed for processes like axonal transport. As axons lack the machinery to synthesize proteins, all necessary proteins have to be transported from the cell body to the periphery. Microtubules which are a basic element of the cytoskeleton play an important role in axonal transport and the maintenance of neurons. [2] They are highly dynamic and polarized structures with a stable minus end and a dynamic plus end. In axons, the plus end is directed away from the soma. [1] Microtubules serve as molecular tracks in neurons to ensure the transport of cargoes to different parts of the cell as well as the clearance of damaged cell organelles. The kinesins are microtubule-based molecular motors and are necessary for the anterograde transport of materials needed for maintenance of axons and synapses. [3, 4] Retrograde transport of degradation products from the axon/synapse back to the cell body is crucial for neuronal maintenance and survival as well. [5] Retrograde transport is carried out by dynein-motorproteins. [6]

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

- Vesicle motility assay: Axoplasm from squid giant axons is isolated and kept in axoplasm buffer. Preparations are analysed using a Zeiss Axiomat and organelle velocities are measured either in an automated process or by matching calibrated cursor movements to the speed of moving vesicles in agreement of two observers. [7-9]

- Kinesin-driven microtubule gliding assay: Slide chambers are covered with kinesins which adhere e.g. to specific antibodies on the glass slides. Rhodamine-labelled tubulin and unlabelled tubulin are mixed and assembled to microtubule structures. Microtubules are applied to the chamber and the rhodamine fluorescence is visualized to evaluate microtubule gliding. Microtubule-bodies are located and tracked to collect data on gliding velocity, trajectory curvature and microtubule length. [7, 10]

- Horseradish peroxidase (HRP) microinjection: HRP is injected into dorsal root ganglia neurons and visualized by 3,3’-diaminobenzidine. Microscope recordings of the neurons showing the transport of HRP are evaluated and the transport length is measured. [11]

- Mitochondrial trafficking: Cells are incubated with drug or DMSO solution and afterwards mitochondria are labelled with MitoTracker Green FM. Cells are kept in a live cell chamber and imaged in regular intervals. The time-lapse is used to track mitochondrial movement in neurites. [12]

- Axonal transport in mouse sciatic nerve: The drug is administered to mice intravenously. Mice are anesthetized and the left sciatic nerve is exposed and ligated at two points. After 24h, the ligated sciatic nerves are dissected and segments from proximal and distal sides of the ligation are collected, homogenized and analysed by Western blot. [12]

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

References

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

1. Baas, P.W., et al., Stability properties of neuronal microtubules. Cytoskeleton (Hoboken), 2016. 73(9): p. 442-60.

2. Hirokawa, N., Axonal transport and the cytoskeleton. Current Opinion in Neurobiology, 1993. 3(5): p. 724-731.

3. Leopold, P.L., et al., Association of kinesin with characterized membrane-bounded organelles. Cell Motility and the Cytoskeleton, 1992. 23(1): p. 19-33.

4. Elluru, R.G., G.S. Bloom, and S.T. Brady, Fast axonal transport of kinesin in the rat visual system: functionality of kinesin heavy chain isoforms. Molecular Biology of the Cell, 1995. 6(1): p. 21-40.

5. Delcroix, J.-D., et al., Trafficking the NGF signal: implications for normal and degenerating neurons, in Progress in Brain Research. 2004, Elsevier. p. 1-23.

6. Susalka, S.J. and K.K. Pfister, Cytoplasmic dynein subunit heterogeneity: implications for axonal transport. Journal of Neurocytology, 2000. 29(11): p. 819-829.

7. 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.

8. Morfini, G., et al., Tau binding to microtubules does not directly affect microtubule‐based vesicle motility. Journal of Neuroscience Research, 2007. 85(12): p. 2620-2630.

9. Morfini, G., et al., JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nature Neuroscience, 2006. 9: p. 907.

10. Peck, A., et al., Tau isoform‐specific modulation of kinesin‐driven microtubule gliding rates and trajectories as determined with tau‐stabilized microtubules. Cytoskeleton, 2011. 68(1): p. 44-55.

11. 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.

12. 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.