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Microtubule-dependent processes precede pathological calcium influx in excitotoxin-induced axon degeneration


Tian, N and Hanson, KA and Canty, AJ and Vickers, JC and King, AE, Microtubule-dependent processes precede pathological calcium influx in excitotoxin-induced axon degeneration, Journal of Neurochemistry pp. 1-14. ISSN 0022-3042 (2019) [Refereed Article]

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Available from 10 November 2020

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Copyright 2019 International Society for Neurochemistry. This is the peer reviewed version of the following article, which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

DOI: doi:10.1111/jnc.14909


Axon degeneration and axonal loss is a feature of neurodegenerative disease and injury and occurs via programmed pathways that are distinct from cell death pathways. While the pathways of axonal loss following axon severing are well described, less is known about axonal loss following other neurodegenerative insults. Here we use primary mouse cortical neuron cultures grown in compartmentalized chambers to investigate the role of calcium in the degeneration of axons that occurs following a somal insult by the excitotoxin kainic acid. Calcium influx has been implicated in both excitotoxicity and axon degeneration mechanisms, however the link between a somal insult and axonal calcium increase is unclear. Live imaging of axons demonstrated that pharmacologically preventing intracellular calcium increases through the endoplasmic reticulum or mitochondria significantly (p < 0.05) reduced axon degeneration. Live calcium-imaging with the Ca2+ indicator Fluo-4 demonstrated that kainic acid exposure to the soma resulted in a rapid, and transient, increase in calcium in the axon, which occured even at low kainic acid concentrations that do not cause axon degeneration within 24 hours. However, this calcium transient was followed by a gradual increase in axonal calcium, which was associated with axonal loss. Furthermore, treatment with a range of doses of the microtubule stabilizing drug taxol, which protects against axon fragmentation in this model, prevented this gradual calcium increase, suggesting that the intra-axonal calcium changes are downstream of microtubule associated events. Biochemical analysis of taxol treated neurons demonstrated a shift in microtubule post-translational modifications, with a significant (p < 0.05) increase in acetylated tubulin and a significant (p < 0.05) decrease in tyrosinated tubulin, suggestive of a more stable microtubule pool. Together our results suggest that axonal degeneration following excitotoxicity is dependent on an increase in axonal calcium, which is downstream of a microtubule dependent event.

Item Details

Item Type:Refereed Article
Keywords:neurodegenerative disease, dementia, ALS, neuroprotection, axon degeneration, calcium signalling, excitotoxin, microtubule
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Cellular Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
UTAS Author:Tian, N (Dr Nan Tian)
UTAS Author:Hanson, KA (Miss Kelsey Hanson)
UTAS Author:Canty, AJ (Associate Professor Alison Canty)
UTAS Author:Vickers, JC (Professor James Vickers)
UTAS Author:King, AE (Professor Anna King)
ID Code:136164
Year Published:2019
Funding Support:National Health and Medical Research Council (1085221)
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2019-12-04
Last Modified:2020-03-27

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