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Event: 1581

Key Event Title

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

Disturbance in microtubule dynamic instability

Short name
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Disturbance in microtubule dynamic instability
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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

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

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

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

Microtubules consist of α- and β-tubulin heterodimer subunits which assemble into protofilaments. These protofilaments further form a hollow cylinder, the microtubule. Microtubules are polar structures due to the head-to-tail assembly of the tubulin heterodimers. The faster growing end of microtubules is called the plus end whereas the slower growing end is the minus end. The plus end is protected from rapid polymerisation by a GTP cap which is a ring of GTP-tubulin . However, when a new tubulin dimer is added to the plus end, GTP gets hydrolysed in the catalytic domain of α-tubulin and the tubulin subunit gets non-exchangeable. [1] Microtubules continuously undergo de- and repolymerization which is summarized as “microtubule dynamic instability”. [2] Microtubules are also stabilized by different proteins like microtubule-associated proteins (MAPs). Microtubule-related proteins often have preferential affinity for specifically modified microtubule regions, which is known as the microtubule code, including post-translational modifications like acetylation, detyrosination or polyamination. [1, 3] Furthermore, microtubules in axons exhibit specific orientation with the plus end pointing away from the soma whereas dendrites show mixed orientation of microtubules. [3] Due to the morphology of peripheral neurons possessing processes that can reach a length of more than one meter, an intact microtubule network is indispensable to ensure the supply of even the most distant parts of the neurites. [4]

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

- Nocodazole approach: Nocodazole is a microtubule-depolymerizing agent. Treatment with nocodazole over different time periods and subsequent quantification of microtubule mass by electron microscopy can give an insight into microtubule stability and the ratio of stabile and labile microtubule fractions. Labile microtubules will be degraded faster while stabile microtubules require more time for depolymerization. [5]

- Immunofluorescence staining for acetylated tubulin, which is a marker for stable microtubules and for tyrosinated tubulin which is a marker of labile microtubules gives insight into the composition of microtubules in cells. [3, 5]

- Fluorescence recovery after photobleaching: Cultured neurons are transfected to express fluorescently-labelled tubulin or injected with x-rhodamine-tubulin (tubulin with fluorescent-label). Multiple sites along a neurite are photobleached and fluorescence recovery after photobleaching was assessed at these sites as a measure for microtubule turnover. [3, 6]

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. Conde, C. and A. Caceres, Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci, 2009. 10(5): p. 319-332.

2. Mitchison, T. and M. Kirschner, Dynamic instability of microtubule growth. Nature, 1984. 312(5991): p. 237-242.

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

4. Griffin, J.W. and D.F. Watson, Axonal transport in neurological disease. Annals of Neurology, 1988. 23(1): p. 3-13.

5. Baas, P.W. and M.M. Black, Individual microtubules in the axon consist of domains that differ in both composition and stability. J Cell Biol, 1990. 111(2): p. 495-509.

6. Edson, K.J., et al., FRAP analysis of the stability of the microtubule population along the neurites of chick sensory neurons. Cell Motil Cytoskeleton, 1993. 25(1): p. 59-72.